Data from Tumor-Derived Complement C3 Overexpression in STK11-Mutant Lung Adenocarcinoma Drives Tumor Growth and Immune Checkpoint Inhibitor Resistance
Year: 2026
Type: other
Abstract: Loss-of-function STK11 mutations occur in 15% to 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 Cancer Cell Line Encyclopedia and The Cancer Genome Atlas datasets, we found that C3 production was increased in human STK11-mutant versus STK11-wildtype (WT) LUAD, modulated by LKB1 loss, whereas high C3 expression in STK11-mutant LUAD was associated with worse survival. STK11 knockout (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 WT 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 WT mice or 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 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 identify therapeutic targets to render these tumors sensitive to anti–PD-1.
Authors: Sora Suzuki, Bojidar Kandar, Catrina Ting, Peter Deraska, Te-An Chen, Thejaswini Giridharan, Anm Nazmul H. Khan, Kristopher Attwood, Han Yu, Kayla Catalfamo, Prashant K. Singh, Ryan T. Bushey, Elizabeth B. Gottlin, Michael J. Campa, Edward F. Patz, Daniel Ajona, Ruben Pio, Brahm H. Segal, Edwin H. Yau
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W7167066423
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