Tripterine Liposome Exerts Antitumor and Immunomodulatory Effects in Pancreatic Ductal Adenocarcinoma

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly aggressive phenotype and limited therapeutic options, primarily attributable to diagnostic delays and intrinsic chemotherapy resistance, thereby underscoring the critical need for the development of more effective therapeutic strategies. Tripterine (TP) is a natural compound with potent antitumor activity, but has shown limited clinical use due to its multi‐organ toxicity. Here, we overcame this limitation by formulating TP into liposomes (TP‐lipo). We evaluated the therapeutic potential of TP‐lipo showing that TP‐lipo exhibited antitumor activity in vitro (murine Pdx1‐Cre / LSL‐Kras G12D/+ / LSL‐Trp53 R172H/+ pancreatic cancer cells, KPC cells) and in vivo (PDAC mouse) models. TP‐lipo reshaped the tumor immune microenvironment by promoting macrophage polarization toward the M1 phenotype, increasing the proportion of interferon‐γ (IFN‐γ)‐secreting CD8 + T cells. In vitro, TP‐lipo promoted IFN‐γ and granzyme B production in CD8 + T cells, while TP‐lipo‐pretreated macrophages enhanced T‐cell differentiation into cytotoxic T lymphocytes. Notably, combination therapy with TP‐lipo and PD‐1 antagonist exerted a synergistic antitumor effect and significantly prolonged median survival in PDAC‐bearing mice. TP‐lipo showed substantially lower toxicity than the free drug, highlighting its improved safety profile and therapeutic potential. Collectively, these findings suggest TP‐lipo, particularly in combination with PD‐1 blockade, as a promising therapeutic strategy for PDAC.