Targeting lactylation and the STAT3/CCL2 axis to overcome immunotherapy resistance in pancreatic ductal adenocarcinoma
Qun Chen, … , Michael S. Bronze, Min Li
Qun Chen, … , Michael S. Bronze, Min Li
Published April 1, 2025
Citation Information: J Clin Invest. 2025;135(7):e191422. https://doi.org/10.1172/JCI191422.
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Commentary

Targeting lactylation and the STAT3/CCL2 axis to overcome immunotherapy resistance in pancreatic ductal adenocarcinoma

Abstract

Metabolic reprogramming in pancreatic ductal adenocarcinoma (PDAC) fosters an immunosuppressive tumor microenvironment (TME) characterized by elevated lactate levels, which contribute to immune evasion and therapeutic resistance. In this issue of the JCI, Sun, Zhang, and colleagues identified nonhistone ENSA-K63 lactylation as a critical regulator that inactivates PP2A, activates STAT3/CCL2 signaling, recruits tumor-associated macrophages (TAMs), and suppresses cytotoxic T cell activity. Targeting ENSA-K63 lactylation or CCL2/CCR2 signaling reprograms the TME and enhances the efficacy of immune checkpoint blockade (ICB) in PDAC preclinical models. This work provides critical insights into the metabolic-immune crosstalk in PDAC and highlights promising therapeutic strategies for overcoming immune resistance and improving patient outcomes.

Authors

Qun Chen, Hao Yuan, Michael S. Bronze, Min Li

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Figure 1

Lactate-induced ENSA-K63 lactylation drives the formation of an immunosuppressive microenvironment in PDAC.

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Lactate-induced ENSA-K63 lactylation drives the formation of an immunosu...
In PDAC cells, lactate, generated by LDH during glycolysis, induces ENSA-K63 lactylation (la), which inhibits PP2A activity and sustains SRC phosphorylation. This activation triggers STAT3 phosphorylation, driving the transcriptional upregulation of CCL2. CCL2 recruits macrophages via CCR2. Separately, extracellular lactate secreted by tumor cells through MCTs is taken up by macrophages, further reprogramming them through the ENSA/SRC/STAT3/CCL2 axis and amplifying the expression of genes encoding immunosuppressive factors (including CCL2, ARG1, S100A9, and IL10). These processes establish an immunosuppressive microenvironment and promote resistance to T cell–mediated antitumor immunity and PD-1–mediated immunotherapy.