The Glycolysis-Lactylation Axis in Immunosuppression and Therapy Resistance in Cancer

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

Summary

Glycolysis, lactylation, and immune suppression: a conceptual bridge in cancer biology:

Context and scope

The immunosuppressive tumor microenvironment (TME) limits the effectiveness of cancer immunotherapy.
Tumor metabolic reprogramming, especially aerobic glycolysis (the Warburg effect), leads to lactate build-up within the TME.
Lactate-derived lysine lactylation (Kla) acts as an epigenetic and post-translational modifier linking metabolic activity to immune cell regulation and tumor cell resilience.

Conceptual framework and mechanisms

The glycolysis-lactylation axis is proposed to orchestrate a multifaceted immunosuppressive program and broad therapy resistance.
Mechanistic facets include: a) suppression of anti-tumor immunity via M2 macrophage polarization, enhanced regulatory T cell (Treg) function, and CD8+ T cell exhaustion; b) increased intrinsic tumor cell resistance through Kla-associated DNA damage repair pathways and maintenance of stem-like features; c) impaired immunotherapy performance, including stabilization of PD-L1 expression.
The review integrates evidence across models to delineate how Kla interfaces with immune and tumor cell processes to sustain an immunosuppressive milieu.

Therapeutic strategies and evidence horizon

Potential interventions target glycolytic enzymes, lactate transporters (MCTs), and enzymes governing lactylation (writers/erasers).
These approaches are discussed for their capacity to synergize with current immunotherapies, with emphasis on preclinical findings.

Clinical translation and gaps

Targeting the lactylation axis represents a metabolic-epigenetic approach aimed at dismantling tumor-driven immunosuppression and mitigating therapy resistance, especially to immunotherapy.
A substantial body of preclinical data supports feasibility, yet clinical translation is limited by evidence hierarchy gaps; prospective trials are needed to validate efficacy and safety.

Limitations and uncertainties

The current synthesis acknowledges reliance on non-clinical models and early-stage data, with explicit gaps in robust human trial evidence acknowledged.