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Here, we sought to identify tumor-intrinsic mediators of KRAS-driven immune evasion and therapeutic resistance in LUAD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Integrated analyses of human LUAD cohorts, genetically engineered mouse models, tumor cell models, and patient-derived organoids were performed to define the role of PRTN3 in immune regulation. PRTN3 regulation and function were investigated using transcriptional analyses, chromatin immunoprecipitation assays, biochemical cleavage assays, and immune cell co-culture systems. The therapeutic effect of PRTN3 inhibition was evaluated using flow cytometric immune profiling, functional immune assays, and syngeneic tumor models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified PRTN3 as a downstream effector of KRAS signaling that promotes immune evasion in LUAD. Mechanistically, KRAS signaling transcriptionally upregulated PRTN3 through c-Myc activation. Secreted PRTN3 directly cleaved and inactivated CXCL9 in the tumor microenvironment, disrupting CXCL9\/CXCR3 signaling and impairing the recruitment and activation of cytotoxic CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and natural killer cells. In patients with LUAD, elevated PRTN3 expression was associated with reduced cytotoxic immune signatures and decreased CXCL9 activity. Genetic inhibition of PRTN3 enhanced antitumor immunity and improved responses to anti-programmed cell death protein 1 therapy in vivo. Furthermore, a hydrolysis-resistant CXCL9 variant restored cytotoxic lymphocyte activation and enhanced immune-mediated tumor cell killing in patient-derived organoids.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings reveal a KRAS\/c-Myc\/PRTN3 axis that promotes immune suppression through extracellular proteolytic inactivation of CXCL9. Targeting PRTN3-mediated immune evasion may represent a promising strategy to enhance ICB efficacy in KRAS-driven LUAD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2026-015399","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:35:38Z","timestamp":1791207338000},"page":"e015399","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["PRTN3 drives immunosuppression in KRAS-mutant lung adenocarcinoma through proteolytic inactivation of CXCL9"],"prefix":"10.1136","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4384-4346","authenticated-orcid":false,"given":"Yi","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Immunology, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China"},{"name":"Nankai University, School of Medicine, Tianjin, 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