Tumor-Intrinsic ARHGEF3 Enhances Antitumor Immunity by Promoting T-Cell Infiltration and Limiting Myeloid Cell-Mediated Immunosuppression.

A lack of effective antitumor T-cell immunity often drives immune evasion and immunotherapy resistance. Here, we demonstrated that tumor-intrinsic ARHGEF3 reprogrammed the tumor microenvironment into a T-cell-inflamed state, resulting in potent antitumor effects. Mechanistically, ARHGEF3 functioned as a guanine nucleotide exchange factor that activated the RHOA-ROCK-PTEN cascade and inhibited AKT signaling. This inhibition upregulated IRF1-dependent chemokines CXCL10 and CXCL11 to drive T-cell infiltration, while suppressing FASN-mediated fatty acid synthesis to limit myeloid cell-mediated immunosuppression. The dual effects elicited robust T-cell immunity and overcame tumor resistance to immunotherapy. In human tumors, ARHGEF3 expression correlated positively with T-cell-inflamed signatures, improved clinical outcomes, and responsiveness to immunotherapy. Collectively, these findings identify ARHGEF3 as a key modulator linking chemokine signaling with lipid availability to shape T-cell immunity, offering a promising therapeutic strategy to overcome immunotherapy resistance.