Retinoic Acid Reprograms Mast Cells Toward a Proinflammatory State to Enhance Antitumor Immunity

  • Adv Sci (Weinh). 2025 Nov 27:e09340. doi: 10.1002/advs.202509340.
Lizao Zhang  1  2 ,  Siqi Ren  1  2 ,  Yuhui Li  2  3 ,  Rongxi Chen  1  2 ,  Ling Qiu  1  2 ,  Yongmei Tan  1  2 ,  Suling Chen  1  2 ,  Huiqian Wu  3 ,  Lianxi Mai  1  2 ,  Xiao Tan  1  2 ,  Xin Liu  4  5 ,  Peisheng Liang  6 ,  Shijia Kuang  1  2 ,  Liansheng Wang  1  2 ,  Jingkang Liu  1  2 ,  Jintao Li  1  2 ,  Yanyan Li  1  2 ,  Qiuping Xu  2  7 ,  Yongzhi Su  8 ,  Yuehai Luo  8 ,  Binyan Wu  8 ,  Zijing Huang  9 ,  Haotian Cao  1  2 ,  Qunxing Li  1  2 ,  Jinsong Li  1  2 ,  Tianjun Lan  1  2
Affiliations
  • 1. Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
  • 2. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
  • 3. Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
  • 4. Department of Stomatology, Affiliated Hospital of Hangzhou Normal University, Hangzhou, 310015, China.
  • 5. Department of Stomatology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, 528308, China.
  • 6. Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Province Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510095, China.
  • 7. Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
  • 8. School of Mathematics and Big Data, Foshan University, Southern Medical University, Foshan 528000, Guangzhou, 510000, China.
  • 9. Department of Endodontics, Stomatological Hospital, Southern Medical University, Guangzhou, 510000, China.
PMID: 41309490 DOI: 10.1002/advs.202509340
Abstract

Mast cells play complex and context-dependent roles within the tumor microenvironment, yet their molecular characteristics and functional diversity across human cancers remain poorly defined. In this study, single-cell RNA Sequencing and spatial transcriptomics data are integrated to comprehensively map the transcriptional and spatial heterogeneity of mast cells across ten Cancer types. A distinct proinflammatory mast cell (PMC) population is identified, characterized by strong antigen-presenting features and immune-activating potential. Mechanistic analyses show that retinoic acid (RA) signaling drives the polarization of PMCs through activation of RARα, which promotes CIITA-mediated MHC-II expression, CXCL16 secretion, and T cell recruitment and activation. Across multiple Cancer types, Tumors with higher PMC abundance are associated with more favorable clinical outcomes. These findings reveal the pivotal role of RA-RARα-CIITA signaling in mast cell reprogramming and suggest that pharmacologic induction of proinflammatory mast cells may represent a promising approach to enhance antitumor immunity.

Keywords
Mast cells; cancer immunotherapy; pan‐cancer; retinoic acid; single‐cell RNA sequencing.
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