Retinoic Acid Reprograms Mast Cells Toward a Proinflammatory State to Enhance Antitumor Immunity
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.
Authors
- Zijing Huang (ORCID: https://orcid.org/0000-0003-2909-2538)
- Jintao Li (ORCID: https://orcid.org/0000-0003-3637-2386)
- Qunxing Li
- Ling Qiu
- Haotian Cao (ORCID: https://orcid.org/0000-0001-5905-4116)
- Jingkang Liu
- Lizao Zhang
- Bo Wu (ORCID: https://orcid.org/0000-0002-9209-5777)
- Rongxi Chen
- Yong Zi Tan
- Shijia Kuang
- Peisheng Liang
- Xiao Tan (ORCID: https://orcid.org/0000-0002-3262-9191)
- Yaxi Luo (ORCID: https://orcid.org/0000-0001-7198-8720)
- Shifang Ren (ORCID: https://orcid.org/0000-0001-8931-9293)
- Xin Liu (ORCID: https://orcid.org/0000-0001-6700-3191)
- Suling Chen
- Yanyan Li (ORCID: https://orcid.org/0000-0002-3572-1858)
- Jinsong Li (ORCID: https://orcid.org/0000-0002-8459-5018)
- Yuhui Li (ORCID: https://orcid.org/0000-0002-6070-5390)
- Yu‐Wen Su (ORCID: https://orcid.org/0000-0001-6730-8219)
- Tianjun Lan (ORCID: https://orcid.org/0000-0002-5680-6164)
- Huiqian Wu
- Qiuping Xu (ORCID: https://orcid.org/0000-0002-4163-6676)
- Lianxi Mai
- Liansheng Wang (ORCID: https://orcid.org/0000-0001-8538-6560)
Institutions
- Foshan University (CN)
- Sun Yat-sen University (CN)
- Guangdong Province Stomatological Hospital (CN)
- Sun Yat-sen Memorial Hospital (CN)
- The First People's Hospital of Shunde (CN)
- Affiliated Hospital of Hangzhou Normal University (CN)
- Stomatology Hospital (CN)
- Southern Medical University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-11-27
- DOI
- https://doi.org/10.1002/advs.202509340
- Primary Topic
- Mast cells and histamine
- Type
- article
- Field-Weighted Citation Impact
- 0.00