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We report that lactylation of the membrane checkpoint ligand CD112 serves as a convergent mechanism for dual immune escape. In contrast to T cell\u2013centric checkpoints such as PD\u2010L1, CD112 functions as a shared inhibitory ligand for both CD8+ T cells and NK cells through TIGIT\/CD112R signaling. Mechanistically, the lactyltransferase AARS2 catalyzes CD112 lactylation at lysine 412 in response to tumor lactate accumulation, competitively blocking the HECT E3 ligase UBE3C to suppress K48\/K63\u2010linked ubiquitination and lysosomal degradation. This stabilizes CD112 at the plasma membrane, enabling tumor cells to coordinately evade both adaptive and innate cytotoxic lymphocytes. Disrupting this axis restores dual immune surveillance and suppresses tumor growth. Tumors with high CD112 lactylation and surface enrichment are selectively vulnerable to TIGIT\/PD\u2010L1 bispecific antibody blockade and HSV\u20102 oncolytic virotherapy, nominating CD112 lactylation status as a predictive biomarker for combination immunotherapy.<\/jats:p>","DOI":"10.1002\/advs.78088","type":"journal-article","created":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T15:40:48Z","timestamp":1791128448000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CD112 Lactylation Drives Dual Immune Evasion From CD8+ T Cells and NK Cells"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8312-2163","authenticated-orcid":false,"given":"Zhuoshuo","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Breast and Thyroid Surgery Union Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 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