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• 1. Introduction

  In the past few decades, photothermal therapy (PTT), which utilizes photothermal conversion agents (PTAs) to ablate tumor tissues, has garnered significant attention in cancer treatment [1–3]. PTT represents an exceptional anticancer approach, offering advantages such as spatiotemporal control, minimally invasive nature, and highly selective tumor cell killing [4,5]. PTT is particularly suitable for treating solid tumors, especially those located superficially. Tumors exhibit lower heat resistance than normal tissues due to their insufficient blood flow, enabling more efficient heat absorption and facilitating effective treatment with minimal side effects [6].

  The rapid advancement of nanotechnology has facilitated extensive investigations of nanomaterial-based PTAs (nano-PTAs) for tumor hyperthermia [7–9]. Numerous promising nano-PTAs have been reported, categorized into metal nanomaterials, carbonaceous nanomaterials, semiconductor nanomaterials, polymer nanoparticles, and organic dye-based nanoparticles [10–12].

  Although PTT can effectively kill tumor cells, its therapeutic efficacy hinges on the delivery efficiency of nano-PTAs. Since the temperature increase is confined to the sites where both PTAs and laser light are present, the uneven distribution of PTAs limits the effectiveness of PTT, often leading to tumor recurrence and metastasis [13]. Thus, PTT efficiency is closely associated with the distribution of PTAs within tumor tissues [14]. Nevertheless, biological barriers impede the efficient intratumoral delivery of PTAs.

  Solid tumors are characterized by an abundant extracellular matrix (ECM), which can constitute up to 60% of tumor tissues [15]. Comprising fibrous proteins, glycoproteins, and glycosaminoglycans [16,17], the tumor ECM proteins form internal crosslinks, creating dense networks with small pores within tumor tissues [18–20]. Simultaneously, the abnormal ECM compresses blood and lymphatic vasculatures, resulting in elevated interstitial fluid pressure and increased tumor mechanical stress [21,22]. This heightened stress mediates the transformation of fibroblasts into cancer-associated fibroblasts (CAFs), which in turn promotes additional ECM production, further increasing tumor stiffness and stress [23]. The steric constraints of the interstitial architecture and the abundance of ECM components severely impede the infiltration of nanoparticles into the tumor core, leading to heterogeneous drug distribution [24–26].

  To overcome these challenges, numerous strategies have been developed to remodel the abnormal tumor ECM, aiming to enhance the penetration of nano-PTAs (Fig. 1) [27–31]. Notably, PTT has been proven to modulate tumor mechanical stress and disrupt dense ECM components, such as collagen fibers [32]. This process improves tumor permeability, facilitating a more uniform distribution of nano-PTAs throughout the tumor mass. However, the complex tumor ECM exhibits diverse responses to elevated temperatures, which may impede nanoparticle diffusion. For instance, although PTT can reduce tumor stiffness, a transient stiffening effect has been observed just after administration [33]. The stromal CAFs can produce collagen, which thus extends the ECM contents. Moreover, the CAFs secreted cytokines, such as transforming growth factor-β (TGF-β), can in turn active CAFs to produce ECM components [34,35]. Emerging evidence indicates that combining PTT with ECM disruption significantly enhances tumor permeability, offering promising strategies to improve intratumoral PTA delivery. Although several reviews have summarized nanoplatform-based strategies for ECM regulation in tumor therapy, to our best of knowledge, rational design of nanoplatforms specifically focus ECM reconstruction for efficient tumor PTT is rarely reviewed. In this review, we summarize recent advances in remodeling the components and structures of the interstitial ECM, which is helpful to enhance PTA permeability. Additionally, we discuss certain considerations and future perspectives for circumventing ECM barriers to achieve effective drug delivery and optimize PTT outcomes.

  Figure 1

  

  Figure 1.  Schematic illustration of diverse strategies of ECM remodeling for enhanced tumor penetration of nano-PTAs.

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  2. Application of nanomaterials in PTT

  PTT is an effective therapeutic strategy that utilizes photothermal PTAs to convert laser energy into heat, thereby inducing tumor cell death [3]. As a minimally invasive treatment with low systemic toxicity, PTT has attracted extensive research attention for cancer treatment owing to its significant advantages. Solid tumors typically exhibit poor blood perfusion, making tumor tissues more susceptible to hyperthermia than normal tissues due to slow heat dissipation [36]. Compared with surgical resection and chemotherapy, light-induced thermal therapy avoids the risk of severe postoperative infections and minimizes systemic side effects [37,38].

  2.1 Nano-PTAs

  With the rapid development of nanomaterials in tumor PTT, researchers have designed various nano-PTAs to enhance therapeutic efficacy (Table S1 in Supporting information) [39–41]. NIR light is predominantly used as the light source because of its low tissue absorption, which enables better tissue transparency and deeper laser penetration [42]. The reduced tissue absorption improves laser irradiation efficiency, facilitating more efficient light-to-heat conversion and thus enhancing tumor ablation by PTT [43].

  Among various nano-PTAs, gold nanosphere is one of the most common photothermal conversion materials [44]. However, the absorption of gold nanospheres is in the range of 500–580 nm, which leads to limited light penetration in tissues and thus hinders the efficient PTT [45]. To address this restriction, some researchers clustered gold nanospheres to redshift the optical absorption to the NIR region. Qu et al. [46] synthesized in-situ stimuli-responsive self-assembled gold nanospheres modified with adenosine monophosphate. The nanostructures are dispersed in water solution with a diameter of 9 nm. However, with the presence of abundant collagen, they immediately aggregate after arriving at tumor sites, and then exhibit pronounced NIR absorption. In vivo experiments demonstrate that the nanostructures induced a 19.9 ℃ higher temperature compared to mono-dispersed gold nanospheres. Some distinctive metal nanomaterials exhibit strong NIR absorption capabilities. For example, Yin et al. [47] developed novel theranostic nanoplatforms consisting of mesoporous silica-coated gold nanostars encapsulated within a gold nanocluster shell. The nanoplatform with a diameter of 99.5 ± 7.2 nm displays high and broad absorption in the NIR region. With multiple "hot spots", it achieves a photothermal conversion efficiency as high as 85.5%.

  It is well-established that NIR irradiation enhances the reachable depth of PTT. However, most current nano-PTAs utilize light in the NIR-Ⅰ region (750–1000 nm). To further increase tissue penetration, the NIR-Ⅱ region (1000–1700 nm) with deeper tissue penetration ability and higher skin permissive laser power density has been extensively studied [48,49]. Gold nanoshell exhibits tunable resonance mode that depend on shell thickness. Thinner gold shells have stronger plasmon hybridization, causing a redshift in the surface plasmon resonance wavelength. By modulating the shell thickness, the maximum NIR absorption of gold nanoshells can be adjusted within the range of 800–1200 nm.

  Despite the variety of metal nano-PTAs, carbonaceous nanomaterials, such as graphenes and carbon nanotubes, are ideal light-heat conversion agents that have been extensively explored for tumor hyperthermia [50]. Recently, Wang et al. [51] utilized graphene oxide nanosheets to treat metastatic tumors, capitalizing on their strong NIR light absorbance and high light-thermal conversion efficiency. Under 808 nm laser irradiation, the temperature increases to 50 ℃ within 105 s and returns to normal levels within 200 s after laser removal, demonstrating a well-controlled PTT.

  Organic NIR dyes, including indocyanine green (ICG), IR780, IR820, and other organic nano-PTAs, have been extensively investigated owing to their excellent properties and low toxicity. For instance, polydopamine has attracted significant attention in PTT due to its broad medical applications. As reported by Zeng et al. [52], mesoporous polydopamine exhibits remarkable photothermal performance. They fabricated a mesoporous polydopamine-based nanoplatform for tumor PTT. Under 808 nm laser irradiation, the temperature of this nanoplatform increases by 30 ℃ within 5 min. Moreover, it demonstrates a high light-thermal conversion efficiency of 36.8%, surpassing that of most other PTAs.

  Other commonly used nano-PTAs include semiconductor nanomaterials such as molybdenum disulfide (MoS₂) and copper sulfide (CuS). Black phosphorus is one of the most outstanding 2D semiconductor nano-PTAs due to its high light-thermal conversion efficiency and excellent biocompatibility [53]. In a previous study by Liang et al. [54], black phosphorus quantum dots were utilized to mediate PTT. Under NIR laser irradiation, the black phosphorus quantum dots demonstrate perfect photothermal performance.

  PTT holds great promise in antitumor treatment. However, several challenges must be addressed before its widespread clinical implementation. One of the most critical concerns is the potential in vivo toxicity of nano-PTAs. The properties of nano-PTAs, including size, shape, surface charge, and modification, significantly influence their biodistributions and toxicities. Recently, surface modification techniques, such as coating with organic polymers or biomembranes, have been widely employed to alter the surface properties of nano-PTAs [55], which can further reduce their toxicity to normal tissues. Moreover, despite the booming development of nano-PTAs, clinical hyperthermia is induced by exciting endogenous chromophores [56]. PTA-based PTT has not been evaluated in large scale clinical trials, because PTAs can only enhance hyperthermia efficacy, but their introduction complicates regulatory processes and elevates development costs. Gold AuroShell nanoparticle is composed of a silica core and gold shell, and it is the only inorganic material approved by U.S. Food and Drug Administration (FDA) for PTT. The clinical trials of gold nanoshells for tumor PTT (NCT04240639, NCT00848042) demonstrate further interest in this area [57].

  2.2 Tumor penetration affected by nano-PTAs properties

  As reported, the properties of nano-PTAs, including particle size, shape, surface charge and modification, significantly affect their diffusion profiles within solid tumors. A large number of studies are devoted to developing size tunable nano-PTAs. Once arriving at the tumor site, the nano-PTAs are triggered to degrade into smaller particles, which have longer tumor penetration distance. Yu et al. [58] reported a nanosystem (NTTD) with in situ "two-step" size transformation ability. The nanosystem was designed to partly reverse the surface charges in tumor acidic condition, which makes the small particles rapidly aggregate to micro-scale, enriching the distribution of nanoparticles in tumor sites. While under 808 nm irradiation, the structure of NTTD is disintegrated, the diameter of which gradually decreases to 21 nm within 10 min irradiation. The reduced size enables the nanoparticle to diffuse into central regions at 100 µm depth of tumor spheroids, enhancing the penetration ability by approximately 4.5-fold.

  The surface charge and modification of nano-PTAs play crucial roles in modulating their penetration efficiency. Positively charged surfaces facilitate nano-PTAs to transport through adsorption-induced transcytosis. Transcytosis can transport cargos through the transcellular pathway. The ATP-dependent transportation allows nano-PTAs to bypass the dense ECM barriers and achieve deep tumor penetration [59]. However, positively charged nanoparticles are more likely to absorb proteins in circulation and cleared by the reticuloendothelial system (RES) before reaching tumor sites. To address this challenge, charge-switchable nanoparticles have been developed to enable both prolonged blood circulation and enhanced deep tumor penetration.

  Recently, the surface modification of nano-PTAs with tumor-homing peptides and cell-penetrating peptides (CPPs) has been extensively investigated to optimize the PTT efficacy. The positive charges of CPPs facilitate nano-PTAs to bind to tumor cells through electrostatic adsorption, thereby triggering active transcellular drug delivery. In recent research, bionic surface modifications have emerged as a promising approach to enhance the tumor penetration of nano-PTAs. Biological membrane-camouflaged nanoparticles can mimic the natural properties and functions of living entities. For example, Chen et al. [60] fabricated NIR-Ⅱ emissive photothermal dye (IRC18)-loaded nanovesicles by hybridizing genetically engineered colony-stimulating factor1 receptor/interleukin 12 (CSF1R/IL12) macrophage membranes with cRGD-decorated liposomes. The macrophage membrane coating enables these nanovesicles to exhibit exceptional tumor infiltration and achieve effective mild PTT.

  3. Tumor ECM destruction via PTT

  3.1 PTT-induced ECM denaturation

  Recently, a substantial of studies have confirmed that PTT can disrupt ECM proteins and melt the ECM [61]. The destruction of collagen fibers increases tumor permeability, thereby facilitating intratumoral diffusion of nano-PTAs. In a previous investigation [62], researchers evaluated the impact of PTT on the ECM of rat colons. When the temperature reaches approximately 66 ℃, submucosal collagen exhibits significant swelling and structural alterations, indicating heat-induced damage to ECM proteins. Chan et al. [63] demonstrated that the gold nanorods-mediated local temperature elevation could denature collagen fibers, effectively opening up the dense ECM network and enabling nanoparticles to penetrate. Notably, even when nano-PTAs fail to reach deep tumor tissues in vivo, PTT-induced collagen denaturation can enhance their diffusion through tumor ECM, ensuring more uniform and efficient hyperthermia throughout solid tumors (Figs. 2H–K).

  Figure 2

  

  Figure 2.  PTT-induced ECM destruction. (A) Illustration of PTT-induced ECM reduction. (B) Schematic diagram and TEM image of the nanosystems. (C) Thermal images of tumor-bearing mice. (D) Temperature changes of nanosystems under irradiation. (E) Immune analysis and (F) quantification of fibronectin and collagen. (G) Tumor stress calculated after different treatments. Reproduced with permission [64]. Copyright 2023, Royal Society of Chemistry. (H) Illustration of the design of the glass µ-chip. (I) Thermal images of the µ-chip during PTT process with gold nanorods installed in the channel. (J) Effect of PTT on diffusion of gold nanoparticles in collagen gels. (K) Penetration depth of gold nanoparticles with 50 nm diameter and 120 nm with PTT. Reproduced with permission [63]. Copyright 2019, Royal Society of Chemistry. (L) Schematic illustration for tumor stress measurement. (M) Images and stress test results of tumors. (N) Modulus map of tumor stiffness after different treatment. (O) Force curves of extend and retract processes of tumor slices. Reproduced with permission [67]. Copyright 2023, Elsevier.

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  3.2 PTT-induced ECM degradation

  In addition, PTT-induced temperature elevation can trigger the degradation of ECM proteins, thereby enhance tumor permeability and facilitate effective drug delivery. Zhang et al. [64] developed hollow mesoporous Prussian blue nanoparticles (HMPB NPs) to achieve deep tumor penetration. The photothermal effect of HMPB NPs maintained the intratumoral temperature between 43 ℃ and 45 ℃. This mild PTT is strong enough to induce collagen degradation and remodel the dense tumor ECM, declining 49.4% after mild hyperthermia. Additionally, the number of activated myofibroblasts is notably lower than that in the control group (Figs. 2A–G). Fang et al. [65] developed nano-PTAs by conjugating gelatin nanoparticles with platinum nanoparticles, with telmisartan (Micardis) loaded within the gelatin shells. They revealed that in combination with telmisartan (Micardis)-mediated TGF-β downregulation, the thermal changes induced by platinum nanoparticles could effectively deplete the tumor ECM. Meanwhile, in the present matrix metalloproteinase (MMP)-2, the gelatin is degraded and the shrunken nanosystems display improved permeating effect due to the depletion of tumor ECM and enlarged gaps of tumor cells in spheroid.

  3.3 PTT-induced ECM soften

  The excessive production and abnormal organization of ECM lead to tumor stiffening and elevated solid stress. These physical barriers severely impede the efficient delivery of anticancer agents within tumor tissues. Numerous studies have shown that PTT can change the tissue mechanics. Marangon et al. [66] investigated tumor stiffness and integrity after carbon nanotubes (CNTs)-mediated PTT. Employing second harmonic generation microscopy (SHG), they found that collagen fibers were not observed nearby CNTs after 30 min and 1-day post-irradiation, implying the damage on collagen structure induced by the local heating. Notably, although tumor sites exhibit transient and reversible stiffening during irradiation, tumor tissues show significant softening in the following days. Xiong et al. [67] utilized atomic force microscopy to evaluate the Young's modulus of tumors. The Young's modulus of tumor sections treated with mild PTT is 22.89 kPa, much lower than that of the control group (42.52 kPa). Moreover, a decreased tumor stress is observed after PTT treatment, which helps normalize blood vessels (Figs. 2L–O).

  In a recent study [68], a nano-regulator based on a peptide-drug conjugate was developed to specifically target fibroblast activation protein-α (FAP-α) overexpressed CAFs. Meanwhile, ICG was loaded in the nano-regular employed to induce hyperthermia. The nano-regulator effectively downregulates the expression of alpha-smooth muscle actin (α-SMA) and FAP-α. Additionally, fibronectin and collagen Ⅰ are significantly reduced after laser irradiation. In combination with ataxia-telangiectasia mutated inhibitor-induced CAF normalization, the nano-regulator causes dysfunction of CAF barriers, further decreasing tumor stiffness and altering ECM structure.

  All these findings demonstrate that nano-based PTAs-induced hyperthermia holds great promise as a strategy to reverse tumor rigidification and normalize tumor vasculature. This, in turn, promotes the deep penetration of nanoparticles and anticancer agents into solid tumors. Furthermore, the photothermal effect can disrupt cell membrane integrity, increasing membrane fluidity and permeability [69]. These changes facilitate active transcellular drug delivery, enhancing the deep diffusion of nano-PTAs and the effectiveness of thermal therapy.

  3.4 PTT-promoted drug penetration in combined therapy

  PTT-induced tumor permeability enhancement can provide enlarged access for the following administrated therapeutics to penetrate into deep tumor tissues [70]. Thus, combined strategies of PTT with other anticancer agents holds promising for achieving ideal treatment outcomes. For instance, researchers developed a photothermal-chemotherapy synergistic strategy by encapsulating the ICG and doxorubicin (DOX) within hybrid nanoparticles. In this system, ICG functions as a PTA, generating heat upon NIR laser irradiation. The temperature in tumors rapidly increases to 54.5 ℃ and displays obvious thermal ablation. Upon laser exposure, the nanoparticles disorganize collagen fibers and decrease the stromal contents. The hyperthermia-induced ECM regulation facilitates a substantial increase in the distribution of DOX within the tumor cores [71]. Li et al. [72] constructed a PTT-improved synergistic strategy by co-loading the antitumor drug celastrol and ICG into nanoparticles composed of poly(N, N–diethyl acrylamide) and poly(2-(diisopropylamino)ethyl methacrylate). Notably, the local temperature elevation triggered by PTT not only enhances the diffusion of nanoparticles but also accelerates the movement of tumor substances. This dual effect enables the drug-loaded nanoparticles to penetrate deeper into tumors, resulting in more effective treatment outcomes. Consequently, these findings underscore the pivotal role of PTT in reshaping the tumor ECM, resolving biological barriers, and promoting the uniform diffusion of the combined therapeutics throughout the entire tumor mass, thereby enhancing the overall efficacy of combined therapies.

  4. ECM regulation-improved PTT

  4.1 ECM destruction

  4.1.1   ECM destruction via physical therapy

  As reported, photodynamic therapy (PDT) can modulate the factor secretions of pancreatic stellate cells (PSCs) and cancer cells, leading to stromal loosening in pancreatic adenocarcinoma [73]. The study reveals that ECM-promoting factors, including TGF-β and connective tissue growth factor (CTGF), as well as ECM proteins such as collagen Ⅰ and fibronectin, are significantly downregulated after PDT. The oxidative damage inflicted by PDT disrupted the paracrine signaling of tumor cells, thereby inhibiting PSC activation. As a result, the PDT treatment caused a significant reduction of 18% total protein content. The significant reduction in ECM proteins highlights the potent anti-stroma effects of PDT, which would provide more favorable pathways for the deep penetration of nanoparticles within solid tumors (Figs. S1A–C in Supporting information).

  Ultrasound therapy using high-intensity focused ultrasound (HIFU) is another optional method that can disrupt the ECM and mediate high tumor permeability for drug delivery. Lee et al. [74] demonstrated that the intensity of HIFU significantly influences tumor structure. They found that the porosity of collagen gels increases in direct proportion to the HIFU intensity. However, exposing tumors to high-intensity HIFU at 10 W and 20 W causes severe damage to the skin near blood vessels, resulting in red blood cell extravasation. In contrast, 5 W pulsed-HIFU effectively degrades collagen and reduces its content in tumor ECM without causing harm to surrounding tissues. More significantly, low-power HIFU increased tumor blood flow, which collectively enhanced the accumulation and extravasation of nanoparticles in tumors. Compared with the control group, the nanoparticles exhibited 2.5-fold higher tumor targeting efficiency.

  Physical therapies, including those mediated by exogenous lasers, ultrasound, or irradiation, regulate the ECM through external energy input. Although the intensity of these physical interventions can be controlled, minor variations may lead to significant differences in ECM regulation outcomes. Therapeutic parameters such as power and treatment duration play crucial roles in determining the effectiveness of ECM modulation and thus require meticulous optimization.

  4.1.2   ECM degradation via enzymolysis

  Collagens are the most abundant components of ECM, possessing about 30% of the total proteins [75]. Modulating collagens is crucial for regulating the characteristics of the tumor ECM. Numerous agents can act on dense collagen in tumors, with MMPs being particularly prominent. MMPs can degrade almost all components of the tumor ECM, transforming the dense network into a more porous state. Among them, collagenase, also known as MMP-8, is widely used to hydrolyze the abundant collagen in the tumor ECM, playing a key role in breaking down the structural integrity of the ECM and facilitating the penetration of therapeutic agents.

  For instance, Yand et al. [76] developed a collagenase-functionalized nanosystem by directly loading collagenase into tumor cell membrane-coated gold nanocages, enabling specific delivery to tumors. Using collagen gels, they evaluated the collagen degradation efficiency of this nanosystem. The results show a dramatic decrease in collagen levels after treatment, and the nanosystem demonstrates significantly enhanced diffusion within collagen gel-loaded capillaries. Inspired by the previous report, Liu et al. [77] fabricated a collagenase-encapsulated metal-organic framework (MOF) for ECM regulation in deep tumor regions for improving photoimmunotherapy. The MOF nanostructure has a high collagenase encapsulation efficiency of up to 80.3%, which effectively enhances tumor permeability through collagenase-mediated ECM degradation. The enlarged ECM gaps provide pathways for immune cells to infiltrate throughout the whole tumor tissues, achieving efficient antitumor outcomes and preventing recurrence (Figs. S1D–I in Supporting information).

  Most endogenous MMPs are secreted as inactive forms by tumor-associated macrophages (TAMs) and require activation through proteolytic cleavage. The inactive precursors of MMPs in tumor ECM can be activated by nitric oxide (NO), and then actively degrade the dense ECM networks [78]. Although MMPs can effectively disorganize the tumor ECM, their non-selective action on normal tissues may lead to undesired side effects. Bromelain is an aqueous protease extracted from pineapple, which shows temperature-sensitive activity. It exhibits optimal collagenolytic activity around 45 ℃ [79], enabling specific ECM degradation in locally heated regions. The elevated temperatures generated by PTT can effectively activate bromelain, facilitating precise digestion of the ECM. Cheng et al. [80] recently engineered bromelain-immobilized polypyrrole nanoparticle (PPy NPs), aiming to enhance drug penetration in tumors. DOX was encapsulated within the surface pores of these PPy NPs, designed for targeted release at approximately 50 ℃ in an acidic tumor microenvironment. By leveraging bromelain's proteolytic activity, PPy NPs efficiently hydrolyze ECM collagen, significantly improving the permeation and attribution of DOX within tumor tissues.

  Hyaluronan (HA) is a major component of the tumor ECM. Hyaluronidase (HAase), an enzyme that specifically hydrolyzes HA, has been approved by the FDA as an adjuvant for subcutaneous fluid administration [81]. Incorporating HAase into nano-PTAs has proven effective in enhancing particle diffusion and antitumor efficacy. Recently, acid-labile MOFs were developed to load HAase and load Ag₂S nanodots. In the acidic tumor microenvironment, the released HAase specifically degraded HA, loosening the ECM and creating gaps for Ag₂S nanodots to pass through the tumor matrix. The uniform distribution of Ag₂S nanodots across the entire tumor enables efficient PTT under NIR-Ⅱ laser irradiation [82]. To improve intratumoral drug deliver efficacy and relieve the HA caused tumor hypoxia, Liu et al. [83] proposed an HA attenuation strategy, utilizing a mesoporous polydopamine (mPDA)-based nanosystem with high light-thermal conversion efficiency to remotely activate endogenous HAase. The heat generated by mPDA not only induces a PTT effect for direct tumor cell killing but also significantly increases HAase activity by approximately 5-folds. The enhancesd HAase activity leads to more efficient depletion of HA, facilitating the penetration of nanoparticles up to 40 µm into the interior of tumor spheroids. Moreover, the combination of PTT and HA degradation effectively reverses the immunosuppressive tumor microenvironment, thereby improving the overall antitumor effect (Figs. S1J–O in Supporting information).

  The degradation of ECM disrupts its three-dimensional network structure and open up access for nano-PTAs to pass through. Unlike the transiently enlarged gaps induced by ultrasound therapy, enzymatic degradation induced tumor permeability may persist over an extended period, which is advantageous for multiple-dose administrations. However, the persistent increasement in ECM permeability is a double-edged sword. It also provides an avenue for tumor cells to escape from the dense tumor ECM and enter the circulatory system, potentially leading to tumor metastasis. In some cases, ECM regulation strategies can cause worse outcomes compared to control groups. Therefore, during ECM manipulation, it is crucial to closely monitor circulating tumor cells, which can help prevent the exacerbation of the disease caused by tumor metastasis.

  4.2 Tumor stromal cell regulation improved PTT

  4.2.1   Cancer-associated fibroblast depletion

  As is well known, the components of the tumor ECM are predominantly secreted by stromal cells, including CAFs, mesenchymal stromal cells (MSCs), and cancer cells [84]. CAFs are important components that contribute the most to construct ECM networks in tumors, and secrete a variety of matrix proteins and cytokines that promote ECM production. Eliminating CAFs is an ideal strategy for enhancing PTT efficiency in anticancer treatment. Numerous CAF-targeting nano-PTAs have been developed to induce CAF depletion, normalize the tumor ECM, and enhance PTT efficacy in cancer treatment. Wang et al. [85] designed hydroxyethyl starch-folic acid conjugates to encapsulate IR780 iodide and DOX prodrug. Besides directly killing tumor cells, IR780 iodide-induced PTT significantly reduces the number of CAFs, leading to a decrease in ECM proteins. Under laser irradiation, the nanomedcine promotes the influx of anticancer agents and oxygen into deep tumor tissues.

  In some other investigations, researchers employed nano-PTAs induced temperature elevation to eliminate CAFs, enhance tumor permeability, and improve the intratumoral distribution of subsequently injected therapeutic agents [86,87]. Such as in a recent study by Li et al. [88], two types of nanogels with distinct stiffness properties were synthesized. The soft nanogels loaded with ICG (ICG@2%NGs) exhibit exceptional deformability. Under 808 nm laser exposure, ICG@2%NGs reduced the proportion of CAFs from 0.3% to 0.1%, and simultaneously, the levels of collagen Ⅰ and fibronectin are significantly decreased. Subsequently, stiff nanogels loaded with DOX (DOX@15%NGs) benefit from ICG@2%NGs-induced tumor permeability, achieving enhanced tumor penetration and more uniform distribution. Notably, compared with thermal ablation, mild hyperthermia with relatively lower temperatures is more effective in expanding blood perfusion, which facilitates the transvascular transportation and thereby improves tumor accumulation (Figs. 3A–E).

  Figure 3

  

  Figure 3.  CAF regulation-induced enlarged tumor penetration for nano-PTA delivery. (A) Illustration of softness-aided hyperthermia regulates tumor mechanics and facilitates the afterwards administrated stiff nanomedicine. (B) Percentage of living CAFs after PTT treatment by ICG-loaded nanogels with different stiffness. (C) Semi-quantitative of fluorescence intensity in tumor spheroid along direction in (D). (D) Penetration of RhB@15%NGs nanogels in tumor spheroids after PTT. (E) Masson, collagen Ⅰ and fibronectin staining of tumor tissues after PTT. Reproduced with permission [88], Copyright 2024, Wiley. (F) Thermal and fluorescence images of tumor-bearing mice after different administration. (G) CD8 and α-SMA staining in tumor tissues after various treatment. (H) α-SMA, fibronectin, and collagen-I and Masson staining of tumor tissues after treatment. (I) Western blot analysis of fibronectin and α-SMA level in myofibroblasts. (J) Relative collagen content in myofibroblasts. (K) Temperature curves of tumor-bearing mice after different treatment. Reproduced with permission [95]. Copyright 2022, Springer Nature. (L) Fluorescence images and flow cytometric analysis of co-cultured 4T1 and NIH/3T3 cells. (M) α-SMA staining of tumor sections treated after Au@Ag. (N) Gene analysis of the genes linked to metastasis-related protein products secreted by CAFs. (O) Half maximal inhibitory concentration (IC₅₀) of 4T1 cells and NIH/3T3 cells after incubation with different metal materials. (P) The ratio of tumor cells to fibroblasts in the tested co-cultures. Reproduced with permission [98]. Copyright 2020, BioMed Central.

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  In addition to PTT, other therapeutic modalities such as PDT and small molecules have also demonstrated efficacy in mediating CAF depletion [89,90]. Bhatt et al. [91] designed a two-dimensional boron nitride (BN) nanosheet with navitoclax decorated on its surface, enabling a combined therapy of PTT and chemotherapy. Navitoclax can specifically deplete CAFs and reduce the excessive protein content in the tumor ECM, even at low doses. Due to the synergistic effect of BCL-2 inhibition and thermal ablation, the levels of proteins in the ECM, particularly B-cell lymphoma/leukemia 2 (BCL-2), connective tissue growth factor (CTGF), and α-SMA, are decreased. This reduction facilitates the diffusion of nanoparticles into the cores of 3D tumor spheroids, achieving a maximum penetration depth of approximately 140 nm. The deep delivery of drugs throughout the entire tumor significantly suppresses tumor proliferation and inhibited distal lung metastasis.

  Although CAF depletion can reduce the ECM and normalize tumor stiffness, the complex roles of CAFs in both tumor suppression and promotion present challenges. Simply eliminating stromal cells may disrupt tumor homeostasis, potentially exacerbating tumor development [92].

  4.2.2   Cancer-associated fibroblast deactivation

  As reported, CAF depletion in pancreatic ductal adenocarcinoma (PDAC) can lead to decreased collagen content and reorganized collagen fibrils, which significantly reduce tumor stiffness and elastic modulus. However, this did not enhance the anticancer efficacy of gemcitabine as anticipated. Instead, they observed that CAF depletion resulted in more invasive, undifferentiated, and necrotic tumors. Furthermore, CAF depletion in PDAC is associated with poorer survival and accelerated tumor progression. These findings demonstrate the dynamic nature of stromal cells during tumor development. Simply depleting CAFs may lead to unpredictable outcomes [93].

  Compared with targeted elimination, CAF deactivation may be a more optical method for antitumor treatment [94]. Li et al. [95] recently developed tumor cell-derived microparticles for co-delivery of calcipotriol and ICG (Cal/ICG@MPs). Calcipotriol is a ligand of vitamin-D receptor and has been found to enhance the lipid droplet storage and transcriptionally deactivate CAFs to a quiescent state, extremally lowering the ability of CAFs to support tumor development. Additionally, calcipotriol significantly decreases the expression levels of fibronectin and α-SMA, further weakening the tumor-supportive functions of CAFs. As a result, Cal/ICG@MPs effectively regulate CAFs and reduce collagen Ⅰ expression in the tumor ECM, leading to enhanced tumor accumulation and diffusion of the encapsulated ICG. Upon NIR laser irradiation, Cal/ICG@MPs demonstrate potent PTT efficacy and remarkable antitumor effects, highlighting the potential of CAF deactivation strategies in cancer treatment (Figs. 3F–K).

  More interestingly, numerous studies have revealed that metal nanoparticles themselves can inhibit tumor growth and metastasis without laser irradiation [96,97]. To explore the underlying mechanism, Kovács et al. [98] evaluated the impact of gold-core silver-shell nanoparticles (Au@Ag) on CAFs. They found that the hybrid nanoparticles induced significant fold changes in the expressions of metallothionein and heme oxygenase. Shh (osteopontin), a protein that promotes cell adhesion, was reduced after treatment with Au@Ag nanoparticles. The nanoparticles also cause significant alterations in gene expression and cytokine secretion in CAFs, which are closely associated with tumor invasion and metastasis, thereby influencing the tumor-promoting activity of the mesenchyme. The Au@Ag nanoparticles decrease the intrinsic crosstalk between CAFs and tumor cells. Notably, no changes were observed in the quantity of α-SMA+ fibroblasts after treatment, suggesting that this approach may improve nanoparticle penetration and delay tumor progression at the same time (Figs. 3L–P).

  4.3 Signaling pathways regulation

  4.3.1   TGF-β

  Recently, reshaping the tumor microenvironment by regulating certain signaling pathways to modulate tumor ECM has become a focus of extensive research [99,100]. TGF-β is a kind of immunosuppressive cytokine that restricts immune cells to infiltrate into solid tumors [101]. It plays a vital role in promoting CAF activation [102]. Studies have reported that reducing TGF-β levels can effectively decrease collagen generation in solid tumors [103,104], significantly improving nanoparticle delivery throughout the tumor mass. Various agents, including losartan, hydralazine, and telmisartan (Micardis), have been utilized to down-regulate the expression level of TGF-β, thereby weakening CAFs and remodeling the tumor ECM [105,106].

  Losartan, a clinically approved angiotensin Ⅱ receptor antagonist for hypertension control, exhibits pronounced antifibrotic activity by blocking TGF-β activation [107–109]. Chen et al. [110] fabricated stress-alleviated nano-PTAs by integrating losartan and IR820 into CaCO₃ nanoparticles. The losartan-induced depletion of collagen Ⅰ in solid tumors substantially reduces tissue stress, enhancing the penetration of the nanoparticles through the tumor ECM. Attributed to the synergistic PTT/PDT effect of IR820 and the improved tumor tissue penetration, the nanoparticles demonstrate potent tumor inhibition. Zhou et al. [111] developed losartan-loaded polydopamine nanoparticles to enhance intratumoral nanoparticle delivery. Losartan was incorporated into polydopamine nanoparticles via π-π stacking, which helped decrease the expression of profibrotic cytokines such as TGF-β1 and tissue inhibitor of metal protease 1 (TIMP-1), thereby reducing collagen synthesis. The synthesized nanoparticles significantly decrease solid stress and facilitate deep diffusion into the tumor parenchyma, notably improving the efficacy of photothermal ablation.

  Curcumin, a polyphenol derived from the Curcuma longa plant, has been recognized as a potent TGF-β inhibitor with outstanding antifibrotic properties [112,113]. Distinct from other TGF-β inhibitors, curcumin not only suppresses tumor growth but also reduces bone metastases by inhibiting osteoclast-induced bone resorption. Owing to these unique characteristics, Shen et al. [114] developed a liquid metal-based nanodrug for efficient PTT in tumor-metastatic bone. The nanodrug significantly decreases TGF-β expression and ECM content. When combined with mild PTT, the released curcumin enables efficient drug delivery into deep tumor tissues, achieving an enhanced penetration depth of approximately 800 µm. Moreover, the nanodrug exhibits significant tumor regression and effectively suppresses the progression of bone metastasis due to the remodeling of the tumor ECM and the inhibition of bone resorption mediated by curcumin (Figs. 4A–E).

  Figure 4

  

  Figure 4.  Signaling pathway regulation-induced enhanced tumor permeability for nano-PTA delivery. (A) Illustration of TGF-β suppression combined with PTT in tumor permeability enlargement. (B) Fluorescence images and (C) semi-quantitative distribution of tumor sections treated with different groups. (D) Fluorescence images of DOX-loaded nanoparticles penetrated into tumor spheroids treated with different formulations. (E) α-SMA, TGF-β, and Masson staining of tumor sections of different treatment groups. Reproduced with permission [114]. Copyright 2023, Wiley. (F) Western blot analysis and (G) mRNA levels of Shh and hypoxia proteins. (H) α-SMA, FAP-α staining and dual-immunofluorescence staining of different treatment groups. (I) LOX immunofluorescence staining of tumor sections. Reproduced with permission [118]. Copyright 2018, Elsevier. (J) Illustration of the peptide nanoparticles (PNP)/siCXCL12/mAb nanosystem induced CAF inactivation. (K) Immunofluorescence staining of α-SMA in CAFs in different groups. (L) Differential cytokine expressions of CAFs detected by proteome array chip. (M) Western blot analysis and (N) quantitative analysis of CXCL12 expression in CAFs. (O) Immunohistochemistry staining and (P) quantitative analysis of α-SMA in tumors. Reproduced with permission [121]. Copyright 2019, ACS.

  DownLoad: Full-Size Img PowerPoint

  4.3.2   Hedgehog (Hh)

  Hh signaling pathway has been reported to play crucial roles in tumorigenesis and fibrosis [115,116]. It is activated in fibroblasts, and acts as a major contributor to ECM deposition. Suppression of the Hh signaling pathway can reduce the number of myofibroblastic CAFs and induce ECM degradation in tumors [117]. Additionally, inhibiting the Hh signaling pathway has been shown to increase tumor sensitivity to chemotherapy, thereby improving patient survival. Previous research has indicated that downregulating FAP-α + CAFs, rather than α-SMA+ CAFs, can inhibit aggressive changes in the tumor ECM and prolong survival. While α-SMA+ CAFs are associated with collagen production, excessive reduction of these cells may lead to poorer prognosis for cancer patients.

  Zhao et al. [118] developed polymeric micelles for the delivery of the Hh inhibitor cyclopamine. In tumor-bearing mouse models, these micelles significantly decrease the mRNA levels of Smo, Ptch1, Gli1, and Shh, which are involved in Hh signaling. The suppression of Hh signaling modestly reduces α-SMA + CAFs, whereas it significantly decreases the FAP-α + CAFs by 56%, accompanied with a 51% decline of HA and a 57% descend of lysyl oxidase (LOX). The constructed nanosystem did not obviously affect the collagen content, but the matrix stiffness was reduced after the treatment, which could retain the tumor-restraining ability of tumor ECM (Figs. 4F–I).

  4.3.3   C-X-C motif chemokine ligand 12 (CXCL12)

  CXCL12 is a CAF secreted factor, which is associated with tumor progression, metastasis, and survival of desmoplastic tumor patients [119]. Meanwhile, the secreted CXCL12, in turn, preserves CAFs as the tumor-promoting phenotype [120]. Therefore, CXCL12 down-regulation is an ideal strategy to deactivate CAFs for enhanced anticancer efficacy. Using CXCL12 silencing siRNA (siCXCL12), Lang et al. [121] downregulated the CXCL12 gene level, which leads to CAF inactivation and decreases secretion of tumor-promoting factors, such as TGF-β, interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF), demonstrating that lower CXCL12 expression could effectively deactivate CAFs and remodel tumor microenvironment (Figs. 4J–O). In a recently published study by He et al. [122], they proposed a nanoplatform composed of Panobinostat-loaded iron/cobalt-based metal-organic framework. By decorating telmisartan (Micardis) on surface, the nanoplarform can actively target to CAFs. After endocytosis by CAFs, the nanoplatform retards CXCL12 secretion and remodels tumor ECM, which is benefit for intratumoral drug penetration. Combined with Panobinostat-induced ferroptosis activation, the nanoplatform displays outstanding tumor elimination by Fenton reaction-mediated ferroptosis, PTT and tumor microenvironment remodeling.

  Signaling pathway regulation is a precise strategy for ECM remodeling, which can accurately control ECM production and degradation. However, the signaling pathways in tumors exhibit multifaceted functions. The regulation of chemokines not only affects ECM permeability but can also trigger a cascade of complex effects within the tumor microenvironment. For example, TGF-β inhibition can indeed reduce CAF activation and subsequently decrease collagen production. Nevertheless, TGF-β exerts a dual-edged influence on tumor progression. Although it has been reported to promote tumor cell invasion, some research has indicated that blocking the TGF-β pathway may unexpectedly induce forestomach carcinoma [123]. The complex roles of cytokines make signaling pathway regulation resulting in an unpredictable result, which should be carefully evaluated in advance.

  4.4 Clinical trials and obstacles of ECM regulation

  ECM regulation strategies have drawn great interest in both preclinical and clinical studies (Table S2 in Supporting information). Pegvorhyaluronidase alpha (PEGPH20) is a HA degrading enzyme. In a phase Ⅰb trial, PEGPH20 was administered to metastatic pancreatic ductal adenocarcinoma (PDAC). Results showed that patients with high-HA tumors had longer survival compared to those with low-HA tumors [124]. A subsequent phase Ⅱ trial assessed the efficacy of PEGPH20 combined with nab-paclitaxel and gemcitabine (AG). Among high-HA tumor patients, the combination therapy achieved an objective response rate (ORR) of 45%, surpassing the 31% ORR of the AG monotherapy group. The median overall survival (OS) of the combination group was 11.5 months, compared to 8.5 months for the AG group [125]. Inspired by these results, a phase Ⅲ trial was performed to compare the treatment outcomes of PEGPH20 + AG and placebo + AG in 492 patients with high HA metastatic PDAC. Although the addition of PEGPH20 increased the ORR, the duration of response and OS were not improved [126]. In another phase Ⅱ clinical trial, the Hh inhibitor IPI-926 was combined with gemcitabine to treat metastatic pancreatic cancer patients. Unfortunately, the treatment outcome fell short of expectations. IPI-926 failed to enhance the efficacy of chemotherapy; instead, the combination strategy resulted in worse clinical outcomes [127].

  Despite showing substantial promise in preclinical investigations, ECM regulation has achieved limited success in clinical trials to date [128]. This discrepancy can be attributed to the multifaceted and intricate roles of ECM in tumor progression. Changes in ECM-associated cytokines and stromal cells can trigger complex responses that do not simply promote or inhibit tumor progression. Therefore, elucidating the underlying mechanisms of ECM remodeling and the dynamic, bidirectional interactions between tumor cells and ECM warrants further in-depth investigation.

  5. Conclusion and perspectives

  Manipulating ECM to improve drug delivery efficiency has been widely used for tumor therapy. Emerging evidence highlights the efficacy of PTT in disrupting the dense ECM network, thereby enabling the uniform distribution of nano-PTAs in tumors. Some studies employed some other strategies to degrade the abundant ECM components in combination with PTT. Moreover, eliminating stromal cells, such as CAFs, shows promising for depleting the ECM. However, disrupting the tumor microenvironment balance may not only boost tumor cell killing but also increase the risk of tumor metastasis. To mitigate this, CAF deactivation has been proposed as an alternative approach for regulating the tumor ECM. This strategy aims to transcriptionally induce CAFs into a quiescent state, thereby reducing their supportive role in tumor growth.

  Although ECM regulation can effectively enhance the tumor penetration of nano-PTAs, several challenges remain to be addressed. Tumor ECM is a complex network composed of hundreds of proteins and cytokines, and its underlying regulatory mechanisms are not fully elucidated. Interventions such as protein fiber disruption, stromal cell depletion, and reduction of tumor rigidity disrupt the tumor microenvironment, potentially leading to unanticipated consequences. In-depth research is required to comprehensively understand the tumor microenvironment. It is worth noting that PTT targets both stromal cells and ECM proteins to facilitate drug penetration. However, excessive ablation may cause vascular collapse, hindering subsequent PTA delivery. Thus, detailed evaluation of tumor PTT parameters is essential to optimize drug delivery.

  Currently, the enhancement of PTT through ECM regulation has been confined to preclinical models, and new advances are urgently needed to realize clinical translation. First, we need to identify the underly mechanisms of ECM remodeling and the interaction between ECM and nano-PTAs; Second, after ECM remodeling, we still need to avoid the hijack of nano-PTAs by stromal cells or macrophages in tumor tissues, which may decrease the particle distribution in tumor core regions; Third, we can design nano-PTAs with instant ECM regulation ability, which can close the space after nanoparticle pass through, avoiding the risk of tumor cell metastasis. It is hoped that this review provides a foundation for basic and preclinical research, ultimately advancing the outcomes of nano-PTA-based PTT in combination with ECM regulation strategies.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Min Zhang: Writing – review & editing, Conceptualization. Ye Chen: Writing – original draft. Yanan Li: Writing – review & editing. Yifan Zhao: Writing – original draft. Bai Lv: Writing – original draft. Jie Cao: Funding acquisition. Bing Yu: Funding acquisition. Hailin Cong: Supervision.

  Acknowledgments

  This work was financially supported by the National Natural Science Foundation of China (Nos. 22074072, 22274083, 32171362), the Natural Science Foundation of Shandong Province (Nos. ZR2022LZY022, ZR2023LZY005, ZR2022YQ73, ZR2021MH087, ZR2024MH070), Special Funds of the Taishan Scholar Program of Shandong Province (No. tsqn202306168), and Traditional Chinese Medicine Science and Technology Project of Shandong Province (No. M-2023124).

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2025.111588.

  
  
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  Figure 1  Schematic illustration of diverse strategies of ECM remodeling for enhanced tumor penetration of nano-PTAs.

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  Figure 2  PTT-induced ECM destruction. (A) Illustration of PTT-induced ECM reduction. (B) Schematic diagram and TEM image of the nanosystems. (C) Thermal images of tumor-bearing mice. (D) Temperature changes of nanosystems under irradiation. (E) Immune analysis and (F) quantification of fibronectin and collagen. (G) Tumor stress calculated after different treatments. Reproduced with permission [64]. Copyright 2023, Royal Society of Chemistry. (H) Illustration of the design of the glass µ-chip. (I) Thermal images of the µ-chip during PTT process with gold nanorods installed in the channel. (J) Effect of PTT on diffusion of gold nanoparticles in collagen gels. (K) Penetration depth of gold nanoparticles with 50 nm diameter and 120 nm with PTT. Reproduced with permission [63]. Copyright 2019, Royal Society of Chemistry. (L) Schematic illustration for tumor stress measurement. (M) Images and stress test results of tumors. (N) Modulus map of tumor stiffness after different treatment. (O) Force curves of extend and retract processes of tumor slices. Reproduced with permission [67]. Copyright 2023, Elsevier.

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  Figure 3  CAF regulation-induced enlarged tumor penetration for nano-PTA delivery. (A) Illustration of softness-aided hyperthermia regulates tumor mechanics and facilitates the afterwards administrated stiff nanomedicine. (B) Percentage of living CAFs after PTT treatment by ICG-loaded nanogels with different stiffness. (C) Semi-quantitative of fluorescence intensity in tumor spheroid along direction in (D). (D) Penetration of RhB@15%NGs nanogels in tumor spheroids after PTT. (E) Masson, collagen Ⅰ and fibronectin staining of tumor tissues after PTT. Reproduced with permission [88], Copyright 2024, Wiley. (F) Thermal and fluorescence images of tumor-bearing mice after different administration. (G) CD8 and α-SMA staining in tumor tissues after various treatment. (H) α-SMA, fibronectin, and collagen-I and Masson staining of tumor tissues after treatment. (I) Western blot analysis of fibronectin and α-SMA level in myofibroblasts. (J) Relative collagen content in myofibroblasts. (K) Temperature curves of tumor-bearing mice after different treatment. Reproduced with permission [95]. Copyright 2022, Springer Nature. (L) Fluorescence images and flow cytometric analysis of co-cultured 4T1 and NIH/3T3 cells. (M) α-SMA staining of tumor sections treated after Au@Ag. (N) Gene analysis of the genes linked to metastasis-related protein products secreted by CAFs. (O) Half maximal inhibitory concentration (IC₅₀) of 4T1 cells and NIH/3T3 cells after incubation with different metal materials. (P) The ratio of tumor cells to fibroblasts in the tested co-cultures. Reproduced with permission [98]. Copyright 2020, BioMed Central.

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  Figure 4  Signaling pathway regulation-induced enhanced tumor permeability for nano-PTA delivery. (A) Illustration of TGF-β suppression combined with PTT in tumor permeability enlargement. (B) Fluorescence images and (C) semi-quantitative distribution of tumor sections treated with different groups. (D) Fluorescence images of DOX-loaded nanoparticles penetrated into tumor spheroids treated with different formulations. (E) α-SMA, TGF-β, and Masson staining of tumor sections of different treatment groups. Reproduced with permission [114]. Copyright 2023, Wiley. (F) Western blot analysis and (G) mRNA levels of Shh and hypoxia proteins. (H) α-SMA, FAP-α staining and dual-immunofluorescence staining of different treatment groups. (I) LOX immunofluorescence staining of tumor sections. Reproduced with permission [118]. Copyright 2018, Elsevier. (J) Illustration of the peptide nanoparticles (PNP)/siCXCL12/mAb nanosystem induced CAF inactivation. (K) Immunofluorescence staining of α-SMA in CAFs in different groups. (L) Differential cytokine expressions of CAFs detected by proteome array chip. (M) Western blot analysis and (N) quantitative analysis of CXCL12 expression in CAFs. (O) Immunohistochemistry staining and (P) quantitative analysis of α-SMA in tumors. Reproduced with permission [121]. Copyright 2019, ACS.

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