Fig. 3

Complex interactions between cancer-associated fibroblasts (CAFs) and T cells. (Figure created with BioRender.com). Myofibroblast CAFs (myCAFs) activate the SMAD2/3-JAK/STAT3 signaling cascade by upregulating TGF-β expression, inducing mesenchymal stem cell differentiation into CAFs and promoting dense extracellular matrix production by CAFs, ultimately blocking T-cell infiltration. They also upregulate CXCL12 expression, recruiting CXCR4⁺ cytotoxic T lymphocytes to the mesenchymal region, preventing T cells from contacting and eliminating cancer cells. Inflammatory CAFs (iCAFs) promote monocyte recruitment and induce their differentiation into M2 macrophages through the CXCL12/CXCR4 or CCL2/CCL2R axis, inhibiting T-cell activation and proliferation. They also recruit myeloma-derived immunosuppressive cells by expressing IL-6 or promote T-cell proliferation in response to T-cell receptor (TCR) stimulation. iCAFs prevent T-cell apoptosis through STAT3-dependent upregulation of anti-apoptotic factors (such as Bcl-2 and Bcl-XL) and regulation of surface expression of Fas receptors. Antigen-presenting CAFs (apCAFs) can induce the conversion of naïve CD4⁺ T cells into regulatory T cells (Tregs) in an antigen-specific manner. They can also cause T-cell incompetence or induce Treg formation by lowering the expression of co-stimulatory molecules (e.g., CD40, CD80, and CD86). apCAFs can directly activate the TCR of effector CD4⁺ T cells and promote T-cell infiltration through the complement pathway (C2, C3, and SERPING1). Furthermore, they can directly inhibit the cytotoxic effects of tumor antigen-specific CD8⁺ T cells by expressing ligands such as PD-L1, PD-L2, and FASL