APOC1 in tumor-associated macrophages enhances protumorigenic M2 polarization and promotes PAAD progression.

Abstract

Apolipoprotein C1 (APOC1) is aberrantly overexpressed in multiple cancers, but its role in pancreatic adenocarcinoma (PAAD) and the tumor microenvironment remains unclear. Here, we investigated the expression and function of APOC1 in tumor-associated macrophages (TAMs) in PAAD. Analysis of public single-cell datasets revealed that APOC1 is predominantly expressed in PAAD-associated macrophages and is significantly upregulated in TAMs compared to M0 macrophages. Functional studies demonstrated that APOC1 promotes M2-polarized immunosuppressive macrophage polarization and consequently enhances PAAD cell proliferation, migration, and resistance to cell death in vitro and in vivo. Mechanistically, APOC1 exerts its effects through two distinct pathways: (i) it activates the PPAR-γ signaling pathway in macrophages to drive M2 polarization; and (ii) it is secreted by macrophages via exosomes and transferred to PAAD cells, where it directly interacts with KEAP1 to stabilize NRF2, leading to suppression of ferroptosis. Targeting APOC1 in TAMs sensitizes PAAD cells to ferroptosis and synergizes with gemcitabine (GEM), a first-line chemotherapeutic agent, as evidenced by enhanced anti-proliferative, anti-migratory, and pro-apoptotic effects in vitro and reduced tumor growth in vivo. Collectively, our findings identify APOC1 as a critical regulator of M2 polarization and ferroptosis resistance in PAAD and suggest that targeting APOC1 in TAMs represents a potential therapeutic strategy to overcome GEM resistance.

Key Findings

• APOC1 is predominantly expressed in tumor-associated macrophages (TAMs) in pancreatic adenocarcinoma (PAAD) and promotes M2 macrophage polarization.
• APOC1 activates PPAR-γ signaling in macrophages to drive M2 polarization and is secreted via exosomes to PAAD cells, where it interacts with KEAP1 to stabilize NRF2, suppressing ferroptosis.
• Targeting APOC1 sensitizes PAAD cells to ferroptosis and enhances the efficacy of gemcitabine chemotherapy, reducing tumor growth and overcoming drug resistance.

Clinical Significance

Citation

Wang Yue, Gao Qing, Xie Yanet al.. APOC1 in tumor-associated macrophages enhances protumorigenic M2 polarization and promotes PAAD progression. Cellular signalling. 2026-Aug-07.