The Glycolysis-Lactylation Axis in Cancer Immunosuppression and Therapy Resistance

14 Apr 20264 min read0 viewsJournal Feed

GIST

BackgroundThe immunosuppressive tumor microenvironment (TME) is a major barrier to the efficacy of cancer immunotherapy. Tumor metabolic reprogramming, particularly aerobic glycolysis (the Warburg effect), drives lactate accumulation in the TIME.

Beyond fueling tumor growth, lactate-derived lysine lactylation (Kla) has emerged as a pivotal epigenetic and post-translational modifier, directly coupling metabolic activity to the regulation of immune cell function and tumor cell resilience.Main bodyThis review synthesizes current evidence to delineate how the glycolysis-lactylation axis orchestrates a multi-faceted immunosuppressive program and confers broad therapy resistance. We detail its mechanisms in: (1) Inhibiting antitumor immunity by driving M2 macrophage polarization, enhancing regulatory T cell (Treg) function, and promoting CD8+ T cell exhaustion; (2) Enhancing intrinsic tumor cell resistance through lactylation-mediated DNA damage repair and stemness maintenance; and (3) Directly undermining immunotherapy, notably by stabilizing programmed cell death 1 ligand 1 (PD-L1).

Clinical Editorial

Context and framework

The immunosuppressive tumor microenvironment poses a major obstacle to cancer immunotherapy.
Tumor metabolic reprogramming, especially aerobic glycolysis, leads to lactate buildup in the tumor ecosystem.
Lactate-derived lysine lactylation (Kla) functions as an epigenetic and post-translational modifier, linking metabolic activity to immune cell behavior and tumor cell resilience.

Study focus and scope

The review assembles current evidence on how the glycolysis-lactylation axis drives a multi-layered immunosuppressive program and broad therapy resistance.
It outlines mechanisms by which Kla influences both immune components and tumor intrinsic properties to hinder anti-tumor responses.

Key mechanistic themes

Immunosuppression within the tumor: Kla promotes M2 macrophage polarization, augments regulatory T cell activity, and contributes to CD8+ T cell exhaustion, collectively dampening antitumor immunity.
Tumor cell intrinsic resistance: Kla is implicated in DNA damage repair pathways and maintains stem-like features that support tumor survival.
Interference with immunotherapy: Kla participates in stabilizing PD-L1, potentially undermining immune checkpoint–targeted strategies.

Therapeutic implications and strategies

Targeting the glycolysis-lactylation axis is explored through approaches such as inhibitors of glycolytic enzymes, lactate transporters (MCTs), and enzymes that write or erase lactylation marks.
The potential for combining these approaches with established immunotherapies is discussed, with emphasis on synergistic effects.

Evidence base and limitations

Preclinical support spans cell line work to patient-derived xenograft models, suggesting feasibility of targeting this axis.
Translation to clinical benefit remains uncertain due to gaps in the evidence hierarchy; prospective clinical trials are needed to validate efficacy and safety.