Cancer-associated fibroblast-derived vascular endothelial growth factor a promotes gastric cancer organoid growth and chemotherapy resistance via paracrine signaling.

Cancer-associated fibroblasts in the lung cancer microenvironment from multi-dimensional mechanisms to therapeutic strategies

Background Lung cancer remains the leading cause of cancer-related mortality worldwide, and therapeutic outcomes are frequently compromised by drug resistance and the complex tumor microenvironment. Although malignant progression is fundamentally driven by genetic alterations, cancer-associated fibroblasts (CAFs) have emerged as critical regulators of tumor progression, immune evasion, and therapeutic resistance. Main body This review systematically summarizes the multidimensional roles of CAFs in lung cancer pathogenesis. CAFs remodel the extracellular matrix to generate high-stiffness stromal barriers, thereby activating the Integrin/Focal adhesion kinase (FAK)/Yes-associated protein (YAP) mechanotransduction axis and impairing drug delivery. Through a multifaceted secretome that includes Interleukin-6 (IL-6), Transforming growth factor-beta (TGF-β), Hepatocyte growth factor (HGF), and C-X-C motif chemokine ligand 12 (CXCL12), CAFs promote epithelial–mesenchymal transition and non-cell-autonomous resistance. Recent single-cell and spatial transcriptomic studies have further revealed functionally distinct CAF subpopulations associated with matrix remodeling, immune exclusion, and therapeutic response. In addition, CAF-derived small extracellular vesicles (sEVs) mediate bidirectional communication with tumor and immune cells, reinforcing tumor plasticity and immune evasion. CAFs also contribute to T-cell exclusion and suppressive myeloid-cell recruitment, thereby attenuating the efficacy of immune checkpoint blockade. Finally, we critically evaluate emerging therapeutic strategies targeting CAF-mediated pathways and discuss their translational opportunities and limitations. Conclusions Overcoming CAF-mediated resistance requires a shift from non-selective stromal depletion toward biomarker-guided stromal normalization and subtype-specific interventions. By integrating mechanistic and translational evidence, this review provides a comprehensive framework for developing more effective precision therapies in lung cancer.

The CAFs-derived YAP1-periostin axis forms a fibrotic tumor microenvironment to promote metastatic lung tumor growth.

BACKGROUND The primary cause of poor prognosis in non-small cell lung cancer (NSCLC) patients is metastasis; however, little is known about the underlying mechanisms mediated by cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME). METHODS We conducted comprehensive molecular and cellular analyses, including RNA sequencing, immunohistochemistry, coculture experiments, and genetic mouse models, to investigate the role of the CD248-periostin-integrin β1 (ITGB1) axis in NSCLC metastasis. RESULTS We demonstrated that CD248+ CAFs are key regulators of NSCLC metastasis. RNA sequencing and clinical sample analysis revealed that CD248 expression in CAFs was positively correlated with increased secretion of periostin (encoded by POSTN). In CAFs, elevated periostin expression is strongly linked to lymph node metastasis (p = 0.002), advanced tumor stage (p = 0.0039), and poor overall survival (p < 0.05) in patients with NSCLC. By promoting the nuclear translocation of YAP1 and regulating POSTN promoter activity to increase periostin expression, CD248 mechanistically causes YAP1 activation in CAFs. According to functional tests, CAFs secreted periostin binds to ITGB1 in NSCLC cells, triggering the FAK/Src signaling pathway to cause epithelial-mesenchymal transition (EMT)-like phenotypic changes and promote NSCLC cell invasion and migration. Additionally, periostin promotes collagen I deposition and increases extracellular matrix (ECM) stiffness, which further amplifies YAP1-driven periostin secretion from CD248+ CAFs, resulting in the formation of a prometastatic positive feedback loop. Fibroblast-specific CD248 deletion or POSTN knockout mice exhibit dramatically reduced metastatic tumor growth in NSCLC in vivo. This is accompanied by decreased ECM stiffness in the TME, decreased EMT-like phenotypic changes, and decreased collagen I deposition. CONCLUSIONS Our results collectively suggested a CD248-YAP1-Periostin-ITGB1 axis that contributes to a prometastatic feedback loop in NSCLC, indicating that focusing on this axis may be a viable therapeutic approach to prevent NSCLC metastasis.

Fibroblasts selectively modulate immune cell-derived cytokine effects on tumor cells in colorectal cancer

Introduction Colorectal cancer (CRC) is a heterogeneous malignancy and a major cause of cancer-related mortality worldwide. Cancer-associated fibroblasts (CAFs) accumulate in tumors and correlate with poor patient survival, suggesting a central role in immune regulation. Patient-derived organoids (PDO) maintain the intra-tumoral cellular heterogeneity of the original tissue, thus, they represent one of the best methods to study human cancers. The tumor microenvironment (TME) contains diverse immune cell populations, including innate lymphoid cells (ILCs), yet how stromal components influence cytokine-driven tumor–immune interactions remains unclear. Methods PDOs from CRC patients were used to screen TME-derived cytokines affecting tumor growth. Organoid-forming efficiency and signaling pathway activation were analyzed following cytokine stimulation in the presence or absence of CAFs. Tumor-infiltrating ILC subsets were characterized in patient samples, and co-culture systems were employed to assess cytokine production and stromal–immune interactions. Results IL-22 was identified as a cytokine that increased PDO-forming efficiency without activating fibroblasts. Although IL-22 typically signals through the JAK–STAT pathway, it unexpectedly activates MAPK signaling in PDO cells. Interestingly, interferon-γ (IFNγ) showed only partial cytotoxic effects on CRC cells. Tumor tissues contained both IFNγ-producing ILC1 and IL-22/IL-17A–producing ILC3 populations. Co-culture with PDOs selectively induced IL-22, but not IL-17A, production in ILC3 cells. Importantly, IL-22 enhanced organoid formation only in the absence of CAFs, whereas IFNγ activity was largely unaffected by stromal context. Discussion These findings demonstrate that CAFs modulate local immunity by selectively masking ILC3-derived IL-22 signaling while preserving ILC1-mediated IFNγ responses. This study emphasizes the importance of stromal context in interpreting cytokine function in CRC and reveals a previously unrecognized mechanism of stromal–immune crosstalk within the TME.

Hypoxia-induced stromal and immune remodeling in gastric carcinoma: correlation of Hypoxia-inducible factor 1-alpha (HIF-1 alpha) expression with cancer-associated fibroblast (CAF) subtypes and Programmed death-ligand 1 (PD-L1) expression

Background: Gastric carcinoma remains a major cause of cancer related mortality worldwide, with tumor progression increasingly recognized as a consequence of complex interactions within the tumor microenvironment. Hypoxia induced signaling, cancer associated fibroblast (CAF) heterogeneity, and immune checkpoint activation play critical roles in tumor progression and immune evasion. However, their integrated relationship in gastric carcinoma remains insufficiently characterized. Objectives: To evaluate the expression of Hypoxia inducible factor 1 alpha and its association with cancer-associated fibroblast subtypes and Programmed death-ligand 1 expression in gastric carcinoma. Methods: This cross sectional analytical study included 100 histologically confirmed gastric carcinoma cases from Satkhira Medical College. Immunohistochemistry was performed for HIF 1 alpha, smooth muscle actin (SMA), fibroblast activation protein (FAP), and PD L1. CAFs were subclassified into myofibroblastic CAFs (myCAFs) and inflammatory CAFs (iCAFs). Associations between biomarkers and clinicopathological variables were analyzed using chi square test, Spearman correlation, and multivariate logistic regression. Receiver operating characteristic (ROC) curve analysis was used to assess model performance. Result: High HIF 1 alpha expression was observed in 55% of cases and demonstrated significant association with poor differentiation (p = 0.001), advanced tumor stage (p = 0.002), and lymph node metastasis (p = 0.001). iCAF predominance was significantly associated with poor differentiation (p = 0.003), advanced stage (p = 0.004), and nodal metastasis (p = 0.004). High PD L1 expression was significantly associated with poor differentiation (p = 0.03), advanced stage (p = 0.001), and lymph node metastasis (p = 0.002). Multivariate logistic regression identified high HIF 1 alpha expression (OR = 3.8, p = 0.001), iCAF dominance (OR = 4.5, p < 0.001), and advanced tumor stage (OR = 2.9, p = 0.004) as independent predictors of high PD L1 expression. Combined high HIF 1 alpha expression and CAF activation demonstrated the highest rate of PD L1 positivity (76.7%, p < 0.001). ROC curve analysis demonstrated good predictive performance of the model with an area under the curve of 0.81. Conclusion: The present study demonstrates a significant interaction between hypoxia, stromal remodeling, and immune checkpoint activation in gastric carcinoma. High HIF 1 alpha expression and inflammatory CAF predominance are strongly associated with aggressive clinicopathological features and increased PD L1 expression, supporting the existence of a coordinated hypoxia stroma immune axis in gastric carcinoma progression. These findings may have potential implications for prognostic stratification and combined targeted therapeutic strategies.

Cancer-Associated Fibroblast-Derived FGF7 Promotes Immune Escape in Oral Squamous Cell Carcinoma via JAK/STAT3-Mediated PD-L1 Expression.

Oral squamous cell carcinoma (OSCC) exhibits high recurrence rates, and immune escape within the tumor microenvironment is a critical barrier to effective therapy. This study investigates whether cancer-associated fibroblast (CAF)-derived FGF7 promotes immune escape in OSCC through JAK/STAT3 pathway-mediated PD-L1. Tumor and adjacent tissues from OSCC patients were analyzed for FGFF7 expression, and the correlations between FGF7 and clinicopathological features were analyzed. CAFs were isolated from OSCC, transfected with plasmids targeting FGF7, and assessed for activation markers, 3D spheroid formation, and epithelial-mesenchymal transition (EMT) proteins. Co-culture systems were established to evaluate the malignant behaviors of OSCC cells exposed to modified CAFs through proliferation, migration, invasion, and apoptosis assays. OSCC cells were co-cultured with CD8+ T cells, followed by measurement of JAK/STAT3 phosphorylation, PD-L1 expression, T-cell activation markers, and immune-related genes. In vivo effects were examined in xenograft models. FGF7 was overexpressed in OSCC tissues and cells, primarily originating from CAFs. FGF7 knockdown in CAFs suppressed activation markers, EMT, and malignant behaviors of OSCC cells. Mechanistically, FGF7 knockdown reduced JAK/STAT3 phosphorylation and PD-L1 expression, impairing T-cell cytotoxicity and antigen presentation. A specific STAT3 inhibitor completely reversed FGF7-induced PD-L1 upregulation. ChIP-qPCR confirmed that STAT3 directly binds to the PD-L1 promoter and activates its transcription. In vivo, CAF-specific FGF7 knockdown attenuated tumor growth and collagen deposition while increasing CD8+ T-cell infiltration and apoptosis. Combined FGF7 knockdown and anti-PD-L1 therapy synergistically enhanced these effects. CAF-derived FGF7 drives immune escape and OSCC progression by upregulating PD-L1 via JAK/STAT3 signaling.

Cancer-associated fibroblast-derived CCL11 promotes prostate cancer malignancy by inducing epithelial-mesenchymal transition via CDK5