{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T12:21:54Z","timestamp":1789042914673,"version":"build-2803163510"},"reference-count":153,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22503063"],"award-info":[{"award-number":["22503063"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["22503063"],"award-info":[{"award-number":["22503063"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Curr. Issues Mol. Biol.","CIMB"],"abstract":"<jats:p>Lysine lactylation (Kla) is a lactate-driven post-translational modification that covalently links lactyl groups to lysine residues, directly coupling cellular metabolic states to gene expression regulation and protein functional remodeling. Since its first report in 2019, extensive studies have confirmed that lactylation is broadly present on histones and thousands of non-histone substrates. In the context of tumor biology, lactylation reinforces glycolysis through positive feedback loops, suppresses oxidative phosphorylation, remodels lipid and glutamine metabolism, and exerts regulatory functions in autophagy, pyroptosis, ferroptosis, and apoptosis, thereby comprehensively participating in tumor cell proliferation, metabolic adaptation, cell death resistance, and invasion and metastasis. Within the tumor microenvironment, lactylation constructs an immune evasion barrier by upregulating immune checkpoints, including programmed death-ligand 1 (PD-L1), driving tumor-associated macrophage polarization toward the M2 phenotype, inducing CD8+ T cell exhaustion, and enhancing regulatory T cell suppressive function. Strategies targeting lactate production (lactate dehydrogenase A (LDHA) inhibitors), lactate transport (monocarboxylate transporter (MCT) inhibitors), and the lactylation enzymatic machinery (p300\/CBP inhibitors, histone deacetylase (HDAC) inhibitors) have shown promising results in preclinical models, and a limited number of agents, including the MCT1 inhibitor AZD3965 and the p300\/CBP inhibitor CCS1477, have entered early-phase clinical trials primarily for safety and tolerability assessment. This review systematically summarizes the molecular mechanisms and enzymatic basis of lactylation, as well as its regulatory functions in core cancer hallmarks and the immune microenvironment, evaluates the translational prospects of targeting the lactate\u2013lactylation axis, and discusses the key scientific questions and future research directions currently facing the field.<\/jats:p>","DOI":"10.3390\/cimb48090926","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T11:38:39Z","timestamp":1789040319000},"page":"926","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lactylation Remodels Tumorigenesis, Immune Microenvironment, and Therapeutic Response"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2154-0142","authenticated-orcid":false,"given":"Yufei","family":"Liu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Separation Membranes and Membrane Processes, School of Chemistry, Tiangong University, Tianjin 300387, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Separation Membranes and Membrane Processes, School of Chemistry, Tiangong University, Tianjin 300387, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiwen","family":"Xue","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Separation Membranes and Membrane Processes, School of Chemistry, Tiangong University, Tianjin 300387, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiru","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Separation Membranes and Membrane Processes, School of Chemistry, Tiangong University, Tianjin 300387, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6878-1059","authenticated-orcid":false,"given":"Yujiao","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Separation Membranes and Membrane Processes, School of Chemistry, Tiangong University, Tianjin 300387, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1113\/JP280955","article-title":"Lactate in Contemporary Biology: A Phoenix Risen","volume":"600","author":"Brooks","year":"2022","journal-title":"J. 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