PRTN3 suppresses cytotoxic immune-cell activation and antitumoral immunity through proteolytic cleavage of CXCL9 in KRAS mutant lung adenocarcinoma

KRAS-mutant lung adenocarcinoma (LUAD) is largely refractory to immune-checkpoint blockade (ICB). Here, we define a novel immune evasion mechanism in KRAS-mutant LUAD mediated by tumor-secreted protease 3 (PRTN3), which proteolytically inactivates the T-cell chemoattractant CXCL9 to create an immune-cold microenvironment. Mechanistically, KRAS signaling transcriptionally upregulates PRTN3 via c-Myc. Secreted PRTN3 then cleaves and inactivates CXCL9 in the tumor microenvironment, thereby disrupting CXCL9/CXCR3 signaling and suppressing the recruitment and activation of cytotoxic NK and CD8+ T cells. In LUAD patients, high PRTN3 expression is associated with low CXCL9 activity. Crucially, genetic ablation of PRTN3 synergizes with anti-PD-1 therapy to restore antitumor immunity in vivo. Moreover, the application of a hydrolysis-resistant CXCL9 variant is sufficient to potently enhance T-cell-mediated killing in LUAD patient-derived organoids, establishing the therapeutic potential of targeting this axis. Our findings establish tumor-derived PRTN3 as a key mediator of immune suppression and a promising therapeutic target in KRAS-driven LUAD.