ONCOGENIC KRAS MUTATIONS ARE THE MOST FREQUENT DRIVER MUTATIONS IN NON-SMALL CELL LUNG CANCER (NSCLC), AND ARE ALSO THE MOST DIFFICULT MUTATIONS TO TARGET. ALTHOUGH TARGETED THERAPY IS NOW AVAILABLE FOR G12C MUTANT KRAS (KRAS-MUT), KRAS INHIBITION IS SHORT-LIVED DUE TO ACQUIRED RESISTANCE AND IMMUNE EVASION. IMMUNE ESCAPE DRIVEN BY ONCOGENIC KRAS PLAYS A CRITICAL ROLE IN DISEASE PROGRESSION. THEREFORE, NOVEL THERAPEUTIC STRATEGIES ARE STILL URGENTLY NEEDED. TARGETING UBIQUITIN-SPECIFIC PEPTIDASE 22 (USP22) IN CANCER MAY MEET THESE NEEDS. USP22 IS OVEREXPRESSED AND STRONGLY ASSOCIATED WITH METASTASIS, RECURRENCE, AND RESISTANCE TO TREATMENT IN VARIOUS CANCERS INCLUDING LUNG CANCER. MOST RECENT STUDIES HAVE FURTHER DEMONSTRATED THAT USP22 STABILIZES PROGRAMMED-DEATH LIGAND-1 (PD-L1) IN CANCER CELLS AND FOXP3 IN T REGULATORY CELLS (TREGS), WHICH LEADS TO AN IMMUNOSUPPRESSIVE MICROENVIRONMENT (TME). AREA(S) OF EMPHASIS: THE PROPOSED STUDIES WILL IDENTIFY INNOVATIVE STRATEGIES FOR THE TREATMENT AND PREVENTION OF RECURRENCE OF LUNG CANCER AND WILL ALSO SIGNIFICANTLY INCREASE OUR UNDERSTANDING OF THE MOLECULAR MECHANISMS OF INITIATION AND PROGRESSION FOR KRAS-MUT LUNG CANCER. OBJECTIVE/HYPOTHESIS: WE FOUND THAT USP22 WAS FREQUENTLY OVEREXPRESSED IN LUNG CANCER AND USP22 KNOCKOUT (USP22-KO) SENSITIZED CANCER CELLS TO CISPLATIN AND IRRADIATION, DRASTICALLY SUPPRESSED IN VIVO ANGIOGENESIS, GROWTH, AND METASTASIS OF KRAS-MUT CANCER XENOGRAFTS AND SIGNIFICANTLY DECREASED BOTH BASIC AND CISPLATIN-INDUCED PD-L1 IN THESE CANCER CELLS. THEREFORE, WE HYPOTHESIZE THAT USP22 IS CRITICAL FOR CARCINOGENESIS AND IMMUNE EVASION OF KRAS-MUT LUNG CANCER AND TARGETING USP22 WILL SUPPRESS CANCER PROGRESSION, SIMULTANEOUSLY BOOST ANTICANCER IMMUNITY, AND SIGNIFICANTLY SENSITIZE