Cancer-associated fibroblasts drive immune resistance in MSS colorectal cancer via the FAIM2-CES1-ER stress pathway.

Microsatellite-stable (MSS) colorectal cancer (CRC) shows limited responsiveness to immune checkpoint inhibitors, often in the context of a fibrotic and immunosuppressive tumor microenvironment. Cancer-associated fibroblasts (CAFs) are central to extracellular matrix (ECM) remodeling, yet the underlying regulatory mechanisms remain unclear. Here, we identify Fas apoptotic inhibitory molecule 2 (FAIM2) as a stromal regulator that is downregulated in MSS CRC and associated with immune infiltration and patient prognosis. Single-cell RNA sequencing localizes FAIM2 predominantly to CAFs, where it inversely correlates with collagen production. Functional studies in L-929 cells and primary CAFs show that FAIM2 overexpression suppresses endoplasmic reticulum (ER) stress signaling and reduces collagen I and matrix metalloproteinase 2 (MMP2) expression; these effects are attenuated by the ER stress inducer Tunicamycin. Conversely, FAIM2 knockdown enhances ER stress and collagen synthesis, which are mitigated by the ER stress inhibitor tauroursodeoxycholic acid (TUDCA). Mechanistically, carboxylesterase 1 (CES1) is identified as a downstream effector negatively regulated by FAIM2, mediating ER stress and ECM remodeling. In vivo, FAIM2 overexpression restrains tumor growth, reduces collagen deposition, and promotes tertiary lymphoid structure (TLS) formation, whereas CES1 co-overexpression counteracts these effects. Together, these findings reveal a potential FAIM2-CES1-ER stress axis in CAFs associated with ECM remodeling and immune contexture in MSS CRC, providing a rationale for future studies exploring its therapeutic potential in immunotherapy.