Tumor-agnostic analysis identified pan-cancer immune archetypes and CD8⁺FoxP3⁺ cells as novel in situ predictors of survival

Immune infiltration shapes anti-tumor responses and is associated with patient outcomes. Yet, comprehensive studies comparing infiltration patterns and their clinical impact across cancer types are scarce.We profiled the tumor immune microenvironment across 16 solid tumor types from more than 2,700 patients using multiplex immunofluorescence with pathologist-curated image analysis to quantify major lymphoid and myeloid subsets and their spatial organization in situ.Across all cancer types, lung, endometrial, and high-grade serous ovarian cancers were highly infiltrated, whereas prostate and ER-positive breast cancers were comparatively “immune cold”. Cancer-agnostic consensus clustering resolved four reproducible immune archetypes with distinct outcomes, including an immune-hot group enriched for CD4, CD8, and B cells that associated with the best survival (p<0.001). Notably, the tumor type accounted for only a part of the immune contexture, as most cancers spanned multiple immune signature groups. Nevertheless, a machine-learning classifier trained on immune compositions distinguished tumor types with high accuracy (AUC = 0.96), confirming that each cancer maintains a recognizable immune imprint even among pan-cancer archetypes.Analysis of survival associations of individual cell classes revealed a rare CD8⁺FOXP3⁺ T-cell phenotype that emerged as a strongest positive prognostic factor across cancers (HR=0.79, 95%CI:[0.70-0.89], p=0.002). Single-cell RNA sequencing data indicated that CD8⁺FoxP3⁺ cells exhibit two distinct gene programs, with regulatory and cytotoxic capacities. Spatial mapping suggested context-dependency in the function of CD8⁺FoxP3⁺ cells, as their proximity to CD8 T cells was linked to better survival (enrichment at 10um: HR=0.76, 95%CI:[0.67-0.90], p=0.0006), whereas proximity to tumor cells was associated with worse prognosis (enrichment at 10um: HR=1.29, 95%CI:[1.12-1.49], p=0.0005).Together, our findings define pan-cancer immune archetypes that are both shared and disease-specific, explaining why “immune hot” and “cold” states are not synonymous with pure infiltration quantities. We identified CD8⁺FoxP3⁺ immune cells as a cell type with strong biomarker potential independent of cancer type.