Cell Reports Medicine
Shiyou Wei (韦诗友)1,33 ∙ Yulan Deng (邓雨岚)1,33 ∙ Jinho Lee2,33 ∙ Hongbin Lan (藍鴻彬)3,33 ∙ Zhenyu Yang (杨振宇)1,33 ∙ Marilyne Labrie4,33 ∙ Courtney B. Betts2,5,33 ∙ Hao Duan (段昊)6 ∙ Benjamin Tate5,7 ∙ Joanna Pucilowska2,7 ∙ Dennie Frederick8 ∙ Aleigha R. Lawless9 ∙ Tatyana Sharova9 ∙ Yuanzhong Yang (杨远忠)10 ∙ Wanming Hu (胡婉明)10 ∙ Georgia M. Beasley11 ∙ Lynn M. Schuchter12,13 ∙ Xiuqi Wang (王修齊)3 ∙ Wei Xu14 ∙ Gen Yong2,15 ∙ Megan E.G. Vandenberg2 ∙ Drew A. Torigian16 ∙ Shamilene Sivagnanam2,5 ∙ Kuang Du17 ∙ Eric Sugarman18 ∙ Suzanne McGettigan12,13 ∙ Cathy Zheng12 ∙ Rami N. Al-Rohil19 ∙ Maria A. Selim19 ∙ Michael B. Datto19 ∙ Giselle Y. López19,20 ∙ Smita K. Nair11 ∙ David M. Ashley20,21 ∙ Xiaowei Xu12,22 ∙ Ravi K. Amaravadi8,12 ∙ Giorgos C. Karakousis23 ∙ Donald M. O'Rourke24 ∙ Steven Brem24 ∙ Bert W. O'Malley25 ∙ Gokhan Demirkan26 ∙ Shuangxing Yu27 ∙ Yiling Lu27 ∙ Todd Camp28 ∙ Janice A. Patterson2,28 ∙ Zhi Wei17 ∙ Christopher Corless2,28 ∙ Dmitry I. Gabrilovich29 ∙ Yonggao Mou (牟永告)6 ∙ Keith T. Flaherty30 ∙ Lisa M. Coussens2,5 ∙ Genevieve Boland9 ∙ Meenhard Herlyn31,32 ∙ Gordon Mills2 ∙ Lunxu Liu (刘伦旭)1 ∙ Gao Zhang (張高)3,34
Published April 21, 2026
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.