Spatial and Functional Characterization of IL1RL1+ Mast Cells Reveals Immune Regulatory Roles in Renal Cancer

Interleukin-1 receptor-like 1 (IL1RL1, also known as ST2) plays a critical role in immune regulation. Pan-cancer analysis has revealed that IL1RL1 is closely associated with cellular immune functions; however, its role in clear cell renal cell carcinoma (ccRCC) and the tumor microenvironment (TME) remains poorly defined. We analyzed IL1RL1 expression patterns using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) were employed to investigate the cellular localization and biological functions of IL1RL1 in ccRCC. In addition, IL1RL1 knockout experiments were conducted to explore its potential role in antigen presentation. Compared to adjacent normal tissues, IL1RL1 expression was significantly downregulated in renal cancer tissues. Higher IL1RL1 expression correlated with improved patient prognosis, suggesting its potential as an independent prognostic biomarker. IL1RL1 was predominantly expressed in mast cells, with higher levels observed in adjacent normal tissues than in tumor tissues, implying a regulatory role in tumor immunity. Subset analysis revealed that IL1RL1-high mast cells were enriched in immune-inflammatory functions, including leukocyte activation, chemokine production, and antigen presentation. Cell-cell communication analysis further demonstrated that IL1RL1+ mast cells may enhance CD8+ cytotoxic T cell activation via the MHC-I signaling pathway. Spatial transcriptomics and multiplex immunohistochemistry (mIHC) confirmed the spatial co-localization of IL1RL1+ mast cells and T cells within the TME. Furthermore, IL1RL1 knockout led to a reduction in HLA-A expression, providing functional evidence for its involvement in antigen presentation. Our findings highlight the immune-regulatory role of IL1RL1+ mast cells in ccRCC. IL1RL1 may contribute to anti-tumor immunity through the modulation of antigen presentation and CD8+ T cell activation, offering new insights into its potential as a prognostic biomarker and therapeutic target in renal cancer.