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<p>Disordered cholesterol–oxysterol profiles are observed in the tumor microenvironment, yet their roles in tumor-associated macrophages (TAMs) remain underexplored. This study reveals that TAMs across human pan-cancers exhibit elevated phosphotyrosine interaction domain-containing protein 1 (PID1) expression and prominent immunosuppressive gene signatures. PID1 deficiency in myeloid cells upregulates low-density lipoprotein (LDL) receptor expression, thereby promoting LDL uptake and intracellular accumulation of free cholesterol and reactive oxygen species (ROS). Increased ROS drives cholesterol oxidation to generate the oxysterols 5α,6α-epoxycholesterol (5α,6α-EC) and 7β-hydroxycholesterol (7β-OHC), which inhibit mTOR–STAT6 signaling in macrophages. <i>Pid1</i> deletion switches immunosuppressive macrophages toward an antitumor subtype that downregulates arginase 1 expression while upregulating proinflammatory cytokines, thereby potentiating CD8<sup>+</sup> T cell-mediated immunosurveillance across multiple tumor types. Moreover, combination treatment with the oxysterol and chemotherapeutic agent 5-fluorouracil produces synergistically enhanced antitumor effects. Previous studies showed that cholesterol-derived oxysterols differentially regulate macrophage cell fates, with 25-OHC promoting the protumor and immunosuppressive phenotype of TAMs. Targeting PID1 reroutes cholesterol and ROS metabolism toward the production of 5α,6α-EC and 7β-OHC in TAMs, representing a promising immunometabolic strategy to restore antitumor immunosurveillance.</p>

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Targeting PID1 generates oxysterols to switch macrophage cell fates for improved antitumor immunity

  • 期刊论文

  • 发表日期：

    2026年6月16日

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  • Yuxiao Zheng,
  • Qi Wang,
  • Chen Dong,
  • Qiong Wang,
  • Mingshun Han,
  • Haiqing Zhao,
  • Shuang Wang,
  • Longlong Chen,
  • Xiaoli Zhang,
  • Dan Yang,
  • Jun Xiao,
  • Zhihuan Chew,
  • Zhenfei Xie,
  • Lei Yang,
  • Jinyong Fan,
  • Xin Zheng,
  • Dezhen Tu,
  • Weiyun Li,
  • Lingming Zheng,
  • Lijian Hui,
  • Xiaowu Huang,
  • Jinsong Li,
  • Huiru Tang,
  • Bin Wei,
  • Hongyan Wang

摘要

Disordered cholesterol–oxysterol profiles are observed in the tumor microenvironment, yet their roles in tumor-associated macrophages (TAMs) remain underexplored. This study reveals that TAMs across human pan-cancers exhibit elevated phosphotyrosine interaction domain-containing protein 1 (PID1) expression and prominent immunosuppressive gene signatures. PID1 deficiency in myeloid cells upregulates low-density lipoprotein (LDL) receptor expression, thereby promoting LDL uptake and intracellular accumulation of free cholesterol and reactive oxygen species (ROS). Increased ROS drives cholesterol oxidation to generate the oxysterols 5α,6α-epoxycholesterol (5α,6α-EC) and 7β-hydroxycholesterol (7β-OHC), which inhibit mTOR–STAT6 signaling in macrophages. Pid1 deletion switches immunosuppressive macrophages toward an antitumor subtype that downregulates arginase 1 expression while upregulating proinflammatory cytokines, thereby potentiating CD8+ T cell-mediated immunosurveillance across multiple tumor types. Moreover, combination treatment with the oxysterol and chemotherapeutic agent 5-fluorouracil produces synergistically enhanced antitumor effects. Previous studies showed that cholesterol-derived oxysterols differentially regulate macrophage cell fates, with 25-OHC promoting the protumor and immunosuppressive phenotype of TAMs. Targeting PID1 reroutes cholesterol and ROS metabolism toward the production of 5α,6α-EC and 7β-OHC in TAMs, representing a promising immunometabolic strategy to restore antitumor immunosurveillance.