Epitranscriptomic Silencing of the ZC3H13/m6A Axis Orchestrates Immunosuppressive Microenvironment Remodeling in Renal Cell Carcinoma via CSF2-Mediated MDSCs Recruitment

Background: The immunosuppressive tumor microenvironment (TME) is a cardinal driver of immune escape and resistance to immunotherapy in renal cell carcinoma (RCC). The N6-methyladenosine (m ⁶ A), the most prevalent RNA modification, critically governs tumor aggressiveness and TME reprogramming. We aimed to exploit whether and how tumor-intrinsic m ⁶ A modification driven by ZC3H13 (zinc finger CCCH-type containing 13) can dictate the immune landscape of RCC. Methods: Loss- and gain-of-function studies were performed in vitro and in allograft tumor model. Tumor-infiltrating immune cells were profiled with flow cytometry and immunostaining. The pivotal cytokine mediated by ZC3H13 depletion was identified through an integrated analysis of RNA-seq, PCR array, and cytokine profiling datasets. The molecular target of ZC3H13 was elucidated through integrated m ⁶ A sequencing and RNA sequencing. Results: Low ZC3H13 expression was an independent predictor of poor prognosis in RCC. Functionally, ZC3H13 silencing enhanced the malignant behaviors of RCC cells and drove an immunosuppressive microenvironment characterized by aberrant recruitment of myeloid-derived suppressor cells (MDSCs). Mechanistically, ZC3H13 promoted m ⁶ A methylation on UNC5CL mRNA, facilitating YTHDC1-mediated stabilization of UNC5CL transcripts, which subsequently suppressed the NF-κB-CSF2 signaling axis, ultimately inhibiting MDSCs accumulation. Furthermore, therapeutic targeting CSF2 significantly increased the efficacy of anti-PD1 blockade in RCC allografts. Conclusion: We identified that ZC3H13 loss unleashes the NF-κB-CSF2 signalling cascade via m ⁶ A-dependent silencing of UNC5CL, converting the RCC milieu into an MDSCs-dominated immunosuppressive niche. Targeting CSF2 may be a novel therapeutic target to improve responses to anti-PD1 immunotherapy in RCC.