Targeting lipid metabolism to overcome immunosuppression and enhance immunotherapy or chemotherapy sensitivity in pancreatic cancer: from immunosuppressive mechanisms to therapeutic opportunities.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by immunosuppressive tumor microenvironment (TME), in which immunosuppression and immune evasion lead to poor response to therapies. Lipid metabolism reprogramming is a central feature of PDAC progression and, depending on the lipid species and context, can promote immunosuppression and immune evasion. Here, we summarize the regulation of lipid metabolism in PDAC and the TME and highlight therapeutic targeting potential. KRAS mutations drive the abnormal activation of key molecules such as SREBP1, FASN, and CD36, promoting de novo fatty acid synthesis, cholesterol metabolism, and the uptake of extracellular lipids. Tumor cells evade immune surveillance by upregulating immune checkpoint molecules and suppressing antigen presentation, thereby impairing both innate and adaptive antitumor immunity. Lipid overload triggers lipid competition and lipotoxicity, induces CD8⁺ T-cell exhaustion and promotes the recruitment of immunosuppressive cells such as M2 macrophages and myeloid-derived suppressor cells. Pancreatic stellate cells and peritumoral adipocytes undergo profound lipid metabolic reprogramming and influence the lipid metabolism of PDAC cells and immune function through mechanisms such as paracrine signaling, thereby further reinforcing the immunosuppressive microenvironment. Lipid metabolism interventions such as targeting fatty acid synthesis, cholesterol metabolism, and lipid peroxidation-driven ferroptosis in combination with chemotherapy and/or immunotherapy have shown promise in preclinical models. Targeting lipid metabolism can reshape the immunosuppressive microenvironment and enhance the sensitivity to PD-1 blockade and gemcitabine, significantly improving antitumor efficacy. In the future, combining spatial metabolomics and single cell lipidomics may reveal the interactions between lipid metabolism and the immune system and explore the mechanisms underlying the lipid metabolic interaction networks among tumor-immune-and stromal cells.

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