Tumor-derived complement C3 overexpression in STK11-mutant lung adenocarcinoma drives tumor growth and immune checkpoint inhibitor resistance.

Loss-of-function STK11 mutations occur in 15-20% of lung adenocarcinomas (LUAD) and correlate with immunotherapy failure and worse survival. By integrating analysis of human tumor samples, a human LUAD cell line panel, and CCLE and TCGA datasets, we found that C3 production was increased in human STK11-mutant versus STK11-wildtype LUAD, modulated by LKB1 loss, while high C3 expression in STK11-mutant LUAD was associated with worse survival. STK11-KO in syngeneic murine LUAD tumors resulted in increased neutrophil and reduced T cell infiltration and anti-PD-1 resistance. STK11-KO tumor growth was similar in C3-/- versus wildtype mice. In contrast, C3 deletion in STK11-KO tumors resulted in dramatic inhibition of tumor growth and enhanced sensitivity to anti-PD-1 in immunocompetent mice but had no significant effect in CD8-depleted wildtype mice or in nude mice, pointing to tumor-derived C3 promoting immune evasion. Mechanistically, STK11 loss drove tumor-derived C3 production and downstream CXCL2 and complement factor H (CFH) production that promoted immune evasion and impaired anti-PD-1 efficacy. Our results show a C3-driven signaling axis for STK11-mutant LUAD promoting immune evasion and identifies therapeutic targets to render these tumors sensitive to anti-PD-1.