Cell

Spatial biology reveals altered macrophage states in immunosuppressed non-melanoma skin cancer

Shorook Naara, Veena Kochat, Xiayu Rao, Emre Arslan, Robert Saddawi-Konefka, Suresh Satpati, Jennifer Garbarino, Jennifer L. Anderson, Frederico O. Gleber-Netto, Priyadharsini Nagarajan, Travis D. Kerr, Shamima Akhter, Sophie Li, R’ay Fodor, Shlomo A. Koyfman, Dan Yaniv, Tongxin Xie, Mica Glaun, Michael Bobian, William Israel Padron, Colin Ng, Preethi H. Gunaratne, Shiyanth Thevasagayampillai, Michael R. Migden, Hussein A. Abbas, Patrick K. Reville, Kenneth Y. Tsai, Daniel J. McGrail, Jing Wang, Jeffrey N. Myers, Neil D. Gross, Kunal Rai, Moran Amit.

Immunosuppressed patients with non-melanoma skin cancer experience worse clinical outcomes, yet the tumor immune microenvironment associated with systemic immunosuppression remains incompletely defined. Using integrated single-cell, spatial transcriptomic, multiplex immunofluorescence, and spatial epigenomic profiling across immunocompetent and immunosuppressed tumors, we found that overall immune-cell composition was largely preserved despite differences in immune-cell distribution, spatial organization, and T cell clonality. Immunosuppressed tumors demonstrated reduced intratumoral macrophage densities, decreased T cell clonal diversity, altered antigen-presenting cell and T cell spatial interactions, and distinct fibroblast- and macrophage-associated spatial niches. Multi-cohort validation across complementary spatial and single-cell platforms identified consistent alterations in innate-adaptive immune organization in immunosuppressed tumors. Together, these findings define spatial and functional remodeling of the tumor immune microenvironment under systemic immunosuppression and provide a framework for future therapeutic investigation in high-risk patients.