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Covalent inhibitors of oncogenic KRAS G12C have demonstrated impressive clinical responses; however, therapeutic resistance has been commonly observed. In this issue, Zhang and colleagues demonstrate that small molecule KRAS G12C inhibitors can generate haptenated major histocompatibility complex (MHC) class I:peptide complexes, which represent attractive targets for immune-based therapies to combat pharmacologic resistance., Competing Interests: Declaration of interests A.J.A. has consulted for Arrakis Therapeutics, Syros Pharmaceuticals, Boehringer Ingelheim, T-knife Therapeutics, AstraZeneca, Mirati Therapeutics, Revolution Medicines, Anji Pharmaceuticals, and Merck & Co., Inc. A.J.A. consults for and holds equity in Riva Therapeutics. A.J.A. has research funding from Mirati Therapeutics, Syros Pharmaceuticals, Bristol Myers Squibb, Revolution Medicines, Novartis, Novo Ventures and Deerfield, Inc. W.A.F-P. has consulted for PMV Pharma and holds equity in Regeneron. W.A.F-P. receives research support from Arcus Biosciences and Apexigen., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high-affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using multiple preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8 + T cells adopt multiple states of dysfunction, resembling those in tumor-infiltrating lymphocytes of PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote immune evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical in maintaining immune evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation., Competing Interests: Declaration of interests T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific, and a co-Founder of Dragonfly Therapeutics and T2 Biosystems. T.J. serves on the Scientific Advisory Board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics. T.J. is also President of Break Through Cancer. His laboratory currently receives funding from Johnson & Johnson and The Lustgarten Foundation; funds from the Lustgarten Foundation supported the research described in this manuscript. A.R. is a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics and until August 31, 2020, was an SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov and Thermo Fisher Scientific. From August 1, 2020, A.R. is an employee of Genentech, a member of the Roche Group. A.R. and Regev lab members' work was conducted at the Broad Institute, unrelated to these later affiliations. T.D.H., P.D., and J.W.R. are employees and stockholders at NanoString Technologies, Inc. None of these affiliations represent a conflict of interest with respect to the design or execution of this study or interpretation of data presented in this manuscript., (Copyright © 2021 Elsevier Inc. All rights reserved.)