International immunopharmacology ·7 Nov 2026 ·Added 10 Nov 2026

APOC1 drives M2 macrophage polarization and prostate cancer progression via PPARG-IL-10 and is targeted by α-NAD.

Tao Ma, Zuorun Xiao, Yueran Chen, Run Ji, Bo Luo, Hongyu Wang, Shipeng Dai, Jiawei Zuo

Other & Emerging Fields

DOI ↗

Abstract

The malignant progression of prostate cancer is closely linked to M2 polarization of macrophages within the tumor microenvironment; however, the upstream molecular drivers that specifically orchestrate this polarization in tumor-associated macrophages (TAMs) remain incompletely understood. This study aimed to investigate the expression profile of apolipoprotein C1 (APOC1) in the prostate cancer microenvironment and elucidate its mechanistic role in modulating macrophage polarization to promote tumor progression. By integrating transcriptomic datasets and single-cell sequencing analyses, along with in vitro macrophage polarization models, co-culture systems, co-immunoprecipitation, GST pull-down assays, dual-luciferase reporter assays, as well as myeloid cell-specific knockout mouse models and pharmacological intervention models, we systematically dissected the function and underlying mechanism of APOC1. Our results demonstrated that APOC1 was consistently overexpressed in prostate cancer tissues and was significantly correlated with shortened progression-free survival in patients. Single-cell analysis and immunofluorescence confirmed that APOC1 was specifically enriched in TAMs. Mechanistically, APOC1 directly bound to PPARG and promoted its nuclear translocation, thereby transcriptionally activating the IL-10 promoter and establishing the APOC1-PPARG-IL-10 signaling axis. Co-culture experiments confirmed that APOC1-modified macrophages facilitated prostate cancer cell proliferation and invasion through paracrine IL-10 secretion. In vivo, both myeloid cell-specific APOC1 knockout and intervention with the APOC1-targeting small-molecule compound α-NAD significantly suppressed tumor growth and induced tumor cell apoptosis. Collectively, this study establishes APOC1 as a critical regulatory factor that drives M2 macrophage polarization to accelerate prostate cancer progression, positioning the APOC1-PPARG-IL-10 axis as a promising immunotherapeutic strategy for prostate cancer.