Eupafolin hinders cross-talk between gastric cancer cells and cancer-associated fibroblasts by abrogating the IL18/IL18RAP signaling axis.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are involved in the progression of gastric cancer (GC) as a critical component of the tumor microenvironment (TME), yet specific interventions remain limited. Natural products hold a promising application prospect in the field of anti-tumor in view of their high activity and ease of binding with biological macromolecules. However, the role of natural products in modulating the cross-talk between CAFs and GC cells has not been fully investigated. PURPOSE: The aim of this study was to identify a potential therapeutic target in CAFs and then screen for natural small molecule drugs with anti-tumor activity against this target. METHODS: Integrating bioinformatics analysis of public databases and experimental validation of human samples and cell lines to identify a candidate target in CAFs. Molecular docking and biolayer interferometry technique were utilized for screening potential natural small molecule drugs. The efficacy and underlying mechanisms of the candidates were explored in vitro and in vivo through techniques such as lentiviral infection, cell spheroids culture, immunoprecipitation and cells-derived xenografts. RESULTS: IL18 receptor accessory protein (IL18RAP) was found to be overexpressed in CAFs derived from GC tissues and facilitated the protumor function of CAFs on GC. Based on virtual screening and experimental validation, we identified a natural product, eupafolin, that interfered with IL18 signaling. Phenotyping studies confirmed that the proliferation, spheroids formation and tumorigenesis of GC cells facilitated by CAFs were greatly attenuated by eupafolin both in vitro and in vivo. Mechanistically, eupafolin impeded the formation of IL18 receptor (IL18R) complex by directly binding to IL18RAP, thus blocking IL18-mediated nuclear factor kappa B (NF-κB) activation and reduced the synthesis and secretion of IL6 in CAFs. As a consequence, it inactivated signal transducer and activator of transcription 3 (STAT3) in GC cells. CONCLUSION: This study provides new evidence that IL18 signaling regulates the cross-talk between GC cells and CAFs. And it highlights a novel pharmacological role of eupafolin in inhibiting IL18 signaling, thereby curbing the development of GC via modulating CAFs.

Developing a Palladium(II) Agent to Overcome Multidrug Resistance and Metastasis of Liver Tumor by Targeted Multiacting on Tumor Cell, Inactivating Cancer-Associated Fibroblast and Activating Immune Response.

To targeted overcome the multidrug resistance (MDR) and metastasis of liver tumors, we proposed to develop a palladium (Pd) agent based on a specific residue of human serum albumin (HSA) for multiacting on tumor cell and other components in the tumor microenvironment. To this end, a series of Pd(II) 2-acetylpyridine thiosemicarbazone compounds were optimized to obtain a Pd(II) compound (5b) with significant cytotoxicity against HepG2/ADM cells. Subsequently, we constructed a HSA-5b complex delivery system and revealed the structural mechanism of HSA delivering 5b. Importantly, 5b/HSA-5b effectively inhibited the growth and metastasis of multidrug resistant liver tumors, and HSA enhanced the targeting ability of 5b and reduced its side effects in vivo. Furthermore, we confirmed the mechanisms of 5b/HSA-5b integrating to overcome MDR and metastasis of liver tumors: multiacting on cancer cell, activating immune response, and inactivating cancer-associated fibroblasts.

Cancer-associated fibroblasts barrier breaking via TGF-ß blockade paved way for docetaxel micelles delivery to treat pancreatic cancer.

TGF-ß is a crucial regulator in tumor microenvironment (TME), especially for myofibroblastic cancer-associated fibroblasts (myCAFs). The myCAFs can be motivated by TGF-ß signaling to erect pro-tumor TME, meanwhile, myCAFs overexpress TGF-ß to mediate the crosstalk between tumor and stromal cells. The blockade of TGF-ß can break cancer-associated fibroblasts barrier, consequently opening the access for drugs into tumor. The TGF-ß is a promising target in anti-tumor therapy. Herein, we introduced a two-stage combination therapy (TC-Therapy), including TGF-ß receptor I inhibitor SB525334 (SB) and cytotoxicity agent docetaxel micelle (DTX-M). We found that SB and DTX-M synergistically inhibited myCAFs proliferation and elevated p53 protein expression in BxPC-3/3T3 mixed cells. Gene and protein tests demonstrated that SB cut off TGF-ß signaling via receptor blockade and it did not arouse TGF-ß legend compensated internal autocrine. On the contrary, two agents combined decreased TGF-ß secretion and inhibited myCAFs viability marked by α-SMA and FAPα. TC-Therapy was applied in BxPc-3/3T3 mixed tumor-bearing mice model. After TC-Therapy, the α-SMA+/ FAPα+ myCAFs faded increasingly and collagenous fibers mainly secreted by myCAFs decreased dramatically as well. More than that, the myCAFs barrier breaking helped to normalize micro-vessels and paved way for micelle penetration. The TGF-ß protein level of TC-Therapy in TME was much lower than that of simplex DTX-M, which might account for TME restoration. In conclusion, TGF-ß inhibitor acted as the pioneer before nano chemotherapeutic agents. The TC-Therapy of TGF-ß signaling inhibition and anti-tumor agent DTX-M is a promising regimen without arising metastasis risk to treat pancreatic cancer. The therapeutic regimen focused on TGF-ß related myCAFs reminds clinicians to have a comprehensive understanding of pancreatic cancer.

Carrier-Free Nanoagent Interfering with Cancer-Associated Fibroblasts' Metabolism to Promote Tumor Penetration for Boosted Chemotherapy.

Elevated production of extracellular matrix (ECM) in tumor stroma is a critical obstacle for drug penetration. Here we demonstrate that ATP-citrate lyase (ACLY) is significantly upregulated in cancer-associated fibroblasts (CAFs) to produce tumor ECM. Using a self-assembling nanoparticle-design approach, a carrier-free nanoagent (CFNA) is fabricated by simply assembling NDI-091143, a specific ACLY inhibitor, and doxorubicin (DOX) or paclitaxel (PTX), the first-line chemotherapeutic drug, via multiple noncovalent interactions. After arriving at the CAFs-rich tumor site, NDI-091143-mediated ACLY inhibition in CAFs can block the de novo synthesis of fatty acid, thereby dampening the fatty acid-involved energy metabolic process. As the lack of enough energy, the energetic CAFs will be in a dispirited state that is unable to produce abundant ECM, thereby significantly improving drug perfusion in tumors and enhancing the efficacy of chemotherapy. Such a simple drug assembling strategy aimed at CAFs' ACLY-mediated metabolism pathway presents the feasibility of stromal matrix reduction to potentiate chemotherapy.

Targeting the cancer cells and cancer-associated fibroblasts with next-generation FGFR inhibitors in prostate cancer co-culture models.

BACKGROUND: Inhibition of androgen receptor (AR) signaling is the main treatment strategy in advanced prostate cancer (PCa). A subset of castration resistant prostate cancer (CRPC) bypasses the AR blockade by increased fibroblast growth factor receptor (FGFR) signaling. The first- and second-generation, non-covalent FGFR inhibitors (FGFRis) have largely failed in the clinical trials against PCa. PURPOSE: In this study, we tested the drug sensitivity of LNCaP, VCaP, and CWR-R1PCa cell lines to second-generation, covalent FGFRis (FIIN1, FIIN2) and a novel FGFR downstream molecule inhibitor (FRS2αi). METHODS: 2D and 3D mono- and co-cultures of cancer cells, and cancer-associated fibroblasts (CAFs) were used to mimic tumor-stroma interactions in the extracellular matrix (ECM). The treatment responses of the FGFR signaling molecules, the viability and proliferation of cancer cells, and CAFs were determined through immunoblotting, migration assay, cell viability assay, and real-time imaging. Immunofluorescent and confocal microscopy images of control and treated cultures of cancer cells and CAFs, and their morphometric data were deduced. RESULTS: The FGFRis were more effective in mono-cultures of the cancer cells compared with co-cultures with CAFs. The FRS2αi was specifically effective in co-cultures with CAFs but was not cytotoxic to CAF mono-cultures as in the case of FIIN1 and FIIN2. At the molecular level, FRS2αi decreased p-FRS2α, p-ERK1/2, and activated apoptosis as monitored by cleaved caspase-3 activity in a concentration-dependent manner in the co-cultures. We observed no synergistic drug efficacy in the combination treatment of the FGFRi with ARi, enzalutamide, and darolutamide. The FRS2αi treatment led to a decrease in proliferation of cancer cell clusters in co-cultures as indicated by their reduced size and Ki67 expression. CONCLUSIONS: CAFs exert a protective effect on cancer cells and should be included in the in vitro models to make them physiologically more relevant in screening and testing of FGFRis. The FRS2αi was the most potent agent in reducing the viability and proliferation of the 3D organotypic co-cultures, mainly by disrupting the contact between CAFs and cancer cell clusters. The next-generation FGFRi, FRS2αi, may be a better alternative treatment option for overcoming ARi treatment resistance in advanced PCa.

The Crosstalk Analysis between mPSCs and Panc1 Cells Identifies CCN1 as a Positive Regulator of Gemcitabine Sensitivity in Pancreatic Cancer Cells.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is almost entirely resistant to conventional chemotherapy and radiation therapy. A significant factor in this resistance appears to be the dense desmoplastic stroma, which contains various cancer-associated fibroblast (CAF) populations. However, our understanding of the communication between tumor cells and CAFs that contributes to this aggressive malignancy is still developing. Recently, we used an advanced three-dimensional heterospecies, heterospheroid co-culture model to investigate the signaling between human pancreatic tumor Panc1 cells and mouse pancreatic stellate cells (mPSCs) through global expression profiling. Upon discovering that CCN1 was significantly upregulated in Panc1 cells during co-culture, we decided to explore the role of CCN1 using CRISPR-Cas9 knockout technology. Panc1 cells lacking CCN1 showed reduced differentiation and decreased sensitivity to gemcitabine, primarily due to lower expression of genes involved in gemcitabine transport and metabolism. Additionally, we observed that stimulation with TGF-ß1 and lysophosphatidic acid increased CCN1 expression in Panc1 cells and induced a shift in mPSCs towards a more myofibroblastic CAF-like phenotype.

Development of Dual Diagnostic-Therapeutic Nanoformulation Effective Against Pancreatic Cancer in Animal Model.

Purpose: Erythrocytes and fibroblasts in the pancreatic cancer tumor microenvironment promote tumor cell growth and invasion by providing nutrients and promoting immunosuppression. Additionally, they form a barrier against the penetration of chemotherapeutic drugs. Therefore, the search for diversified tumor-targeting materials plays an essential role in solving the above problems. Methods: Physicochemical characterization of Graphene fluorescent nanoparticles (GFNPs) and nanomedicines were analyzed by transmission electron microscopy (TEM), elemental analyzers and ultraviolet fluorescence (UV/FL) spectrophotometer. Localization of GFNPs in cell and tissue sections imaged with laser confocal microscope, fluorescence scanner and small animal in vivo imager. Qualitative detection and quantitative detection of GFNPs and GFNPs-GEM were performed using High performance liquid chromatography (HPLC). Results: Based on the 3 nm average dimensions, GFNPs penetrate vascular endothelial cells and smooth muscle cells, achieve up to label 30% tumor cells and 60% cancer-associated fibroblasts (CAFs) cells, and accurately label mature red blood cells in the tumor microenvironment. In orthotopic transplanted pancreatic cancer models, the fluorescence intensity of GFNPs in tumors showed a positive correlation with the cycle size of tumor development. The differential spatial distribution of GFNPs in three typical clinical pancreatic cancer samples demonstrated their diagnostic potential. To mediate the excellent targeting properties of GFNPs, we synthesized a series of nanomedicines using popular chemotherapeutic drugs, in which complex of GFNPs and gemcitabine (GFNPs-GEM) possessed stability in vivo and exhibited effective reduction of tumor volume and fewer side effects. Conclusion: GFNPs with multiple targeting tumor microenvironments in pancreatic cancer possess diagnostic efficiency and therapeutic potential.

Unlocking the potential: Targeting metabolic pathways in the tumor microenvironment for Cancer therapy.

Cancer incidence and mortality are increasing and impacting global life expectancy. Metabolic reprogramming in the tumor microenvironment (TME) is intimately related to tumorigenesis, progression, metastasis and drug resistance. Tumor cells drive metabolic reprogramming of other cells in the TME through metabolic induction of cytokines and metabolites, and metabolic substrate competition. Consequently, this boosts tumor cell growth by providing metabolic support and facilitating immunosuppression and angiogenesis. The metabolic interplay in the TME presents potential therapeutic targets. Here, we focus on the metabolic reprogramming of four principal cell subsets in the TME: CAFs, TAMs, TILs and TECs, and their interaction with tumor cells. We also summarize medications and therapies targeting these cells' metabolic pathways, particularly in the context of immune checkpoint blockade therapy.

Anakinra-Loaded Sphingomyelin Nanosystems Modulate In Vitro IL-1-Dependent Pro-Tumor Inflammation in Pancreatic Cancer.

Pancreatic cancer is a very aggressive disease with a dismal prognosis. The tumor microenvironment exerts immunosuppressive activities through the secretion of several cytokines, including interleukin (IL)-1. The IL-1/IL-1 receptor (IL-1R) axis is a key regulator in tumor-promoting T helper (Th)2- and Th17-type inflammation. Th2 cells are differentiated by dendritic cells endowed with Th2-polarizing capability by the thymic stromal lymphopoietin (TSLP) that is secreted by IL-1-activated cancer-associated fibroblasts (CAFs). Th17 cells are differentiated in the presence of IL-1 and other IL-1-regulated cytokines. In pancreatic cancer, the use of a recombinant IL-1R antagonist (IL1RA, anakinra, ANK) in in vitro and in vivo models has shown efficacy in targeting the IL-1/IL-1R pathway. In this study, we have developed sphingomyelin nanosystems (SNs) loaded with ANK (ANK-SNs) to compare their ability to inhibit Th2- and Th17-type inflammation with that of the free drug in vitro. We found that ANK-SNs inhibited TSLP and other pro-tumor cytokines released by CAFs at levels similar to ANK. Importantly, inhibition of IL-17 secretion by Th17 cells, but not of interferon-γ, was significantly higher, and at lower concentrations, with ANK-SNs compared to ANK. Collectively, the use of ANK-SNs might be beneficial in reducing the effective dose of the drug and its toxic effects.

Rhein and hesperidin nanoparticles remodel tumor immune microenvironment by reducing CAFs and CCL2 secreted by CAAs for efficient triple-negative breast cancer therapy.

In triple-negative breast cancer (TNBC), the tumor immune microenvironment (TIME) is a highly heterogeneous ecosystem that exerts indispensable roles in tumorigenesis and tumor progression. Cancer-associated fibroblasts (CAFs) and cancer-associated adipocytes (CAAs) are the main matrix components in the TIME of TNBC. CAFs mediate the edesmoplastic response, which is a major driver of the immunosuppressive microenvironment to promote tumor growth. In addition, CAAs, a type of tumor-educated adipocyte, participate in crosstalk with breast cancer and are capable of secreting various cytokines, adipokines and chemokines, especially C-C Motif Chemokine Ligand 2 (CCL2), resulting in changes of cancer cell phenotype and function. Therefore, how to treat tumors by regulating the CAFs and the secretion of CCL2 by CAAs in TIME is investigated here. Our research group previously found that rhein (Rhe) has been identified as effective against CAFs, while hesperidin (Hes) could effectively diminish CCL2 secretion by CAAs. Inspired by the above, we developed unique PLGA-based nanoparticles loaded with Rhe and Hes (RH-NP) using the emulsion solvent diffusion method. The RH-NP particles have an average size of 114.1 ± 0.98 nm. RH-NP effectively reduces CAFs and inhibits CCL2 secretion by CAAs, promoting increased infiltration of cytotoxic T cells and reducing immunosuppressive cell presence within tumors. This innovative, safe, low-toxic, and highly effective anti-tumor strategy could be prospective in TNBC treatment.

Metformin suppresses esophageal cancer progression through the radiation­induced cellular senescence of cancer­associated fibroblasts.

Senescent cells are known to secrete proteins, including inflammatory cytokines and damage­associated molecular patterns. This phenomenon is known as the senescence­associated secretory phenotype (SASP). SASP in cancer stromal fibroblasts is involved in cancer growth and progression. Conversely, metformin, an antidiabetic drug, has been reported to inhibit SASP induction by inhibiting the activation of NF­κB, a regulator of SASP. To date, at least to the best of our knowledge, there have been no reports regarding cellular senescence in fibroblasts and tumor progression via the SASP­mediated paracrine pathway. The present study thus aimed to elucidate the induction mechanisms of SASP in radiation­induced fibroblasts and to determine its effects on cancer progression via the paracrine pathway. Furthermore, the present study aimed to determine whether controlling SASP using metformin suppresses cancer progression. A well­differentiated esophageal cancer cell line established by the authors' department and fibroblasts isolated and cultured from the non­cancerous esophageal mucosa of resected esophageal cancer cases were used for the experiments. Fibroblasts were irradiated with 8 Gy radiation, and the changes in the expression of the senescence markers, SA­ß­gal, p21, p16 and NF­κB were evaluated using immunofluorescent staining and western blot analysis in the presence or absence of metformin treatment. The culture supernatants of irradiated fibroblasts treated with metformin and those treated without metformin were collected and added to the cancer cells to evaluate their proliferative, invasive and migratory abilities. Vimentin and E­cadherin expression levels were also evaluated using immunofluorescent staining and western blot analysis. The expression levels of p16, p21 and NF­κB in irradiated fibroblasts were attenuated by treatment with metformin. Supernatants collected from irradiated fibroblasts exhibited the proliferative activity of esophageal cancer cells, and the promotion of migratory and invasion abilities, which may be due to epithelial­mesenchymal transition and changes in cell morphology. These reactions were confirmed to be suppressed by the addition of the supernatant of cultured fibroblasts pre­treated with metformin. On the whole, the present study demonstrates that fibroblasts in the cancer stroma may be involved in tumor progression through cellular senescence.

Combining gemcitabine and MSC delivering soluble TRAIL to target pancreatic adenocarcinoma and its stroma.

Pancreatic ductal adenocarcinoma (PDAC) still has a poor response to therapies, partly due to their cancer-associated fibroblasts (CAFs). Here, we investigate the synergistic impact of a combinatory approach between a known chemotherapy agent, such as gemcitabine (GEM), and gene-modified human mesenchymal stromal/stem cells (MSCs) secreting the pro-apoptotic soluble (s)TRAIL (sTRAIL MSCs) on both PDAC cells and CAFs. The combo significantly impacts on PDAC survival in 2D and 3D models. In orthotopic xenograft models, GEM and sTRAIL MSCs induce tumor architecture shredding with a reduction of CK7- and CK8/18-positive cancer cells and the abrogation of spleen metastases. A cytotoxic effect on primary human CAFs is also observed along with an alteration of their transcriptome and a reduction of the related desmoplasia. Collectively, we demonstrate a promising therapeutic profile of combining GEM and sTRAIL MSCs to target both tumoral and stromal compartments in PDAC.

Multicompartment Polyion Complex Micelles Based on Triblock Polypept(o)ides Mediate Efficient siRNA Delivery to Cancer-Associated Fibroblasts for Antistromal Therapy of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and the third leading cause for cancer-related death worldwide. The tumor is difficult-to-treat due to its inherent resistance to chemotherapy. Antistromal therapy is a novel therapeutic approach, targeting cancer-associated fibroblasts (CAF) in the tumor microenvironment. CAF-derived microfibrillar-associated protein 5 (MFAP-5) is identified as a novel target for antistromal therapy of HCC with high translational relevance. Biocompatible polypept(o)ide-based polyion complex micelles (PICMs) constructed with a triblock copolymer composed of a cationic poly(l-lysine) complexing anti-MFAP-5 siRNA (siMFAP-5) via electrostatic interaction, a poly(γ-benzyl-l-glutamate) block loading cationic amphiphilic drug desloratatine (DES) via π-π interaction as endosomal escape enhancer and polysarcosine poly(N-methylglycine) for introducing stealth properties, are generated for siRNA delivery. Intravenous injection of siMFAP-5/DES PICMs significantly reduces the hepatic tumor burden in a syngeneic implantation model of HCC, with a superior MFAP-5 knockdown effect over siMFAP-5 PICMs or lipid nanoparticles. Transcriptome and histological analysis reveal that MFAP-5 knockdown inhibited CAF-related tumor vascularization, suggesting the anti-angiogenic effect of RNA interference therapy. In conclusion, multicompartment PICMs combining siMFAP-5 and DES in a single polypept(o)ide micelle induce a specific knockdown of MFAP-5 and demonstrate a potent antitumor efficacy (80% reduced tumor burden vs untreated control) in a clinically relevant HCC model.

Single-cell transcriptomic insights into chemotherapy-induced remodeling of the osteosarcoma tumor microenvironment.

PURPOSE: Neoadjuvant chemotherapy serves as an effective strategy for treating osteosarcoma (OS) not only by targeting cancerous cells but also by influencing the tumor's immune and stromal elements. Gaining insights into how chemotherapy reshapes the tumor's local environment is crucial for advancing OS treatment protocols. METHODS: Using single-cell RNA sequencing, this study analyzed tumor samples from patients with advanced osteosarcoma collected both before and after chemotherapy. RESULTS: The results revealed that chemotherapy caused the remaining OS cells to express higher levels of genes associated with stemness. Additionally, this process enhances the presence of cancer-associated fibroblasts, increasing their ability to modify the extracellular matrix (ECM). Chemotherapy also increases the number of endothelial cells, albeit with compromised differentiation capabilities. Importantly, the treatment reduced the immune cell population, including myeloid and T/NK cells, particularly impacting the subpopulations with tumor-fighting capabilities. CONCLUSION: These findings highlight the complex reaction of the tumor environment to chemotherapy, providing valuable insights into how chemotherapy influences OS cells and the tumor microenvironment (TME). This knowledge is essential for understanding OS resistance mechanisms to treatments, potentially guiding the development of novel therapies for managing advanced OS.

Breaking Down Barriers in Drug Delivery by Stromal Remodeling Approaches in Pancreatic Cancer.

Pancreatic cancer remains a formidable challenge in oncology due to its aggressive nature and limited treatment options. The dense stroma surrounding pancreatic tumors not only provides structural support but also presents a formidable barrier to effective therapy, hindering drug penetration and immune cell infiltration. This review delves into the intricate interplay between stromal components and cancer cells, highlighting their impact on treatment resistance and prognosis. Strategies for stromal remodeling, including modulation of cancer-associated fibroblasts (CAFs), pancreatic stellate cells (PSCs) activation states, and targeting extracellular matrix (ECM) components, are examined for their potential to enhance drug penetration and improve therapeutic efficacy. Integration of stromal remodeling with conventional therapies, such as chemotherapy and immunotherapy, is discussed along with the emerging field of intelligent nanosystems for targeted drug delivery. This comprehensive overview underscores the importance of stromal remodeling in pancreatic cancer treatment and offers insights into promising avenues for future research and clinical translation.

Effect of Bioactive Black Phosphorus Nanomaterials on Cancer-Associated Fibroblast Heterogeneity in Pancreatic Cancer.

Tumor-stromal interactions and stromal heterogeneity in the tumor microenvironment are critical factors that influence the progression, metastasis, and chemoresistance of pancreatic ductal adenocarcinoma (PDAC). Here, we used spatial transcriptome technology to profile the gene expression landscape of primary PDAC and liver metastatic PDAC after bioactive black phosphorus nanomaterial (bioactive BP) treatment using a murine model of PDAC (LSL-KrasG12D/+; LSL-Trp53R172H/+; and Pdx-1-Cre mice). Bioinformatic and biochemical analyses showed that bioactive BP contributes to the tumor-stromal interplay by suppressing cancer-associated fibroblast (CAF) activation. Our results showed that bioactive BP contributes to CAF heterogeneity by decreasing the amount of inflammatory CAFs and myofibroblastic CAFs, two CAF subpopulations. Our study demonstrates the influence of bioactive BP on tumor-stromal interactions and CAF heterogeneity and suggests bioactive BP as a potential PDAC treatment.

Cancer-associated fibroblasts mediate resistance to anti-EGFR therapies in cancer.

Over the last decade, epidermal growth factor receptor (EGFR)-targeted therapies have transformed the treatment landscape for patients with advanced solid tumors. Despite these advances, resistance to anti-EGFR therapies is still a significant clinical challenge. While cell-autonomous mechanisms of resistance are well-documented, they do not fully elucidate the complexity of drug resistance. Cancer-associated fibroblasts (CAFs), key mediators within the tumor microenvironment (TME), have emerged as pivotal players in cancer progression and chemoresistance. Recent evidence implicates CAFs in resistance to anti-EGFR therapies, suggesting they may undermine treatment efficacy. This review synthesizes current data, highlighting the critical role of CAFs in resistance pathogenesis and summarizing recent therapeutic strategies targeting CAFs. We underscore the challenges and advocate for the exploration of CAFs as a potential dual-targeted approach.

TSG-6+ cancer-associated fibroblasts modulate myeloid cell responses and impair anti-tumor response to immune checkpoint therapy in pancreatic cancer.

Resistance to immune checkpoint therapy (ICT) presents a growing clinical challenge. The tumor microenvironment (TME) and its components, namely tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), play a pivotal role in ICT resistance; however, the underlying mechanisms remain under investigation. In this study, we identify expression of TNF-Stimulated Factor 6 (TSG-6) in ICT-resistant pancreatic tumors, compared to ICT-sensitive melanoma tumors, both in mouse and human. TSG-6 is expressed by CAFs within the TME, where suppressive macrophages expressing Arg1, Mafb, and Mrc1, along with TSG-6 ligand Cd44, predominate. Furthermore, TSG-6 expressing CAFs co-localize with the CD44 expressing macrophages in the TME. TSG-6 inhibition in combination with ICT improves therapy response and survival in pancreatic tumor-bearing mice by reducing macrophages expressing immunosuppressive phenotypes and increasing CD8 T cells. Overall, our findings propose TSG-6 as a therapeutic target to enhance ICT response in non-responsive tumors.

CAFs and T cells interplay: The emergence of a new arena in cancer combat.

The interaction between the immune system and the tumor matrix has a huge impact on the progression and treatment of cancer. This paper summarizes and discusses the crosstalk between T cells and cancer-associated fibroblasts (CAFs). CAFs can also produce inhibitors that counteract the function of T cells and promote tumor immune escape, while T cells can also engage in complex two-way interactions with CAFs through direct cell contact, the exchange of soluble factors such as cytokines, and the remodeling of the extracellular matrix. Precise targeted intervention can effectively reverse tumor-promoting crosstalk between T cells and CAFs, improve anti-tumor immune response, and provide a new perspective for cancer treatment. Therefore, it is important to deeply understand the mechanism of crosstalk between T cells and CAFs. This review aims to outline the underlying mechanisms of these interactions and discuss potential therapeutic strategies that may become fundamental tools in the treatment of cancer, especially hard-to-cure cancers.