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 and immunosuppressed patients. Our results challenge the prevailing notion that immunosuppression is primarily driven by reduced immune cell abundance or lymphocytic dysfunction. Instead, we identified a critical deficiency in antigen presentation by macrophages, leading to impaired T-cell diversity and clonal expansion. Additionally, a spatial epigenomic atlas of the NMSC TME revealed distinct spatial niches and epigenetic programs associated with immunosuppression. 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.