A longitudinal, multi-omic atlas reveals the emergence of a spatially organized immunosuppressive ecosystem in resistant melanoma
Cell Reports Medicine
Shiyou Wei (韦诗友), Yulan Deng (邓雨岚), Jinho Lee, Hongbin Lan (藍鴻彬), Zhenyu Yang (杨振宇), Marilyne Labrie, Courtney B. Betts2, Hao Duan (段昊), Benjamin Tate, Joanna Pucilowska, Dennie Frederick, Aleigha R. Lawless, Tatyana Sharova, Yuanzhong Yang (杨远忠), Wanming Hu (胡婉明), Georgia M. Beasley, Lynn M. Schuchter, Xiuqi Wang (王修齊), Wei Xu, Gen Yong, Megan E.G. Vandenberg, Drew A. Torigian, Shamilene Sivagnanam, Kuang Du, Eric Sugarman, Suzanne McGettigan, Cathy Zheng, Rami N. Al-Rohil, Maria A. Selim, Michael B. Datto, Giselle Y. López, Smita K. Nair, David M. Ashley, Xiaowei Xu, Ravi K. Amaravadi, Giorgos C. Karakousis, Donald M. O’Rourke, Steven Brem, Bert W. O’Malley, Gokhan Demirkan, Shuangxing Yu, Yiling Lu, Todd Camp, Janice A. Patterson, Zhi Wei, Christopher Corless, Dmitry I. Gabrilovich, Yonggao Mou (牟永告), Keith T. Flaherty, Lisa M. Coussens, Genevieve Boland, Meenhard Herlyn, Gordon Mills, Lunxu Liu (刘伦旭), Gao Zhang (張高)
Summary
Despite advances in immune checkpoint blockade, resistance in metastatic melanoma remains a major challenge. To decode resistance mechanisms, we generate a comprehensive longitudinal, multi-omic, and spatial atlas of 45 tumor samples across 10 patients. Analysis reveals resistant tumors undergo convergent evolution toward a shared, spatially organized immunosuppressive ecosystem. We identify a structural mechanism characterized by spatial partitioning of immune checkpoints, where B7-H3 dominates MITF-high niches while IDO1 characterizes MITF-low zones. Furthermore, integrated single-cell and spatial analysis identifies a specific malignant subclone (c1) and a distinct architectural niche (RCN3), both exhibiting aberrant PI3K-mTOR signaling. Notably, c1 promotes the “ignored tumor” phenotype via FN1-ITGB1 and GDF15 signaling. Validated across independent cohorts, these spatial and molecular signatures predict poor survival and point to actionable targets. Ultimately, our study elucidates the spatial logic of resistance and provides a rationale for translating multi-omic discoveries into actionable, personalized therapeutic strategies.
Citation
Wei, Shiyou, et al. “A longitudinal, multi-omic atlas reveals the emergence of a spatially organized immunosuppressive ecosystem in resistant melanoma.” Cell Reports Medicine 7.4 (2026).