FAP fibroblasts promote C1QC macrophage infiltration via WNT2 signaling to exacerbate T cell exhaustion in oral squamous cell carcinoma.

The crosstalk between cancer-associated fibroblasts (CAFs) and immune cells drives immunosuppressive tumor microenvironment (TME) in oral squamous cell carcinoma (OSCC), but the underlying mechanisms remain poorly understood. Here, we identified fibroblast activation protein (FAP)-expressing CAFs as the key orchestrators of immunosuppression through WNT2-mediated reprogramming of C1QC macrophages. Thus, we utilized single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, in vitro and in vivo functional assays to investigate the role of FAP fibroblasts in modulating TME. Co-culture systems and multi-omics analyses were employed to dissect stromal-immune crosstalk. Our study demonstrated that FAP expression escalated during OSCC progression and correlated with poor prognosis. According to OSCC animal model and single-cell RNA sequencing, the inhibition of FAP reshaped the immune landscape, notably reducing infiltration of C1QC macrophages, which localized proximally to FAP fibroblasts in clinical specimens. Mechanistically, FAP fibroblasts secreted WNT2 to activate β-catenin signaling in macrophages, upregulating C1QC and M2 markers. This FAP-WNT2-C1QC axis conferred tumor-promoting functions. Further analysis demonstrated that C1QC macrophages exhibited tumor-promoting functions, including enhanced fatty acid metabolism and immunosuppressive signaling. They secreted CCL2 to recruit Tregs, and induced T cell exhaustion. Crucially, FAP expression predicted resistance to anti-PD-1 therapy, and its inhibition enhanced the efficacy of anti-PD-1 treatment in OSCC. Overall, our findings unveil stromal FAP fibroblasts as central regulators of macrophage-dependent immunosuppression via WNT2 signaling, proposing a novel therapeutic target to reprogram the TME in OSCC.