Spatial biology reveals macrophage dysfunction in immunosuppressed non-melanoma skin cancer

The rising incidence of non-melanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), particularly among immunosuppressed individuals, underscores the need for a deeper understanding of the tumor microenvironment (TME) to develop effective and safe immunotherapies. This study employed single-cell multi-omic analyses to investigate the spatial distribution and transcriptional profiles of immune cells in NMSC from both immunocompetent (IC) and immunosuppressed (IS) patients. Our results challenge the prevailing notion that immunosuppression is primarily driven by reduced immune cell abundance or lymphocytic dysfunction. We found that IS tumors retain all requisite immune cell populations but display functional suppression and disrupted spatial organization. Our data revealed a limited number of distinct programs, particularly in macrophages and their spatially organized niches, that are linked to restricted T-cell repertoire diversity and impaired clonal expansion, providing a mechanistic bridge between innate dysfunction and adaptive immune failure. These perturbations were further confirmed by a novel spatial epigenomic atlas of the NMSC TME that revealed immune status–specific regulatory programs, including MAF- and ATF3-driven macrophages and CUX1- enriched fibroblast niches, that shape the epigenetic landscape of immunosuppressed tumors. These findings highlight the central role of innate immunity in shaping anti-tumor responses and offer potential therapeutic targets to enhance immunotherapy in this vulnerable patient population.