(A) Heatmap of samples’ Danaher leukocyte RNA signatures, ordered by the mean across all signatures (the TIL-score). (B) Heatmap of genes associated with IFN-γ signaling (23), ordered by mean expression the IFN-γ signature. (C) Box plots of Z-scores of CD8⁺ T cell and IFN-γ signatures per ICI response category (responders, green; nonresponders, red). (D) Enrichment analysis of Hallmark gene sets (32) in responders and nonresponders, ordered by FDR. (E) Heatmap visualizing TIDE signatures (33) associated with CAFs, MDSCs, and TAMs in all patients from the more-infiltrated cluster defined in Figure 3D. Heatmap is organized by the mean across the 3 signatures. (F) Box plots of TIDE signature values in responders vs. nonresponders from the more-infiltrated cluster. (G) Box plots displaying the TGF-β signatures in responders vs. nonresponders from the more-infiltrated cluster. (H) Box plot visualizing the mIF-assessed stromal CD8⁺ T cell density in responding vs. nonresponding samples from the more-infiltrated cluster. Tracks in A, B, and E annotate sample’s primary site of origin and best objective response, with asterisks indicating tumprs that progressed in the context ofa mixed response. Boxes in C and F–H indicate the median and IQR; with whiskers extending up to 1.5 times the IQR. Exact P values in C and F–H were calculated using a Wilcoxon’s rank-sum test. Dot colors represent samples’ site of primary MucM origin. H&N, head and neck; SN, sinonasal; OC, oral cavity, FUT, female urogenital tract; MUT, male urogenital tract; AR, anorectal; GI, gastrointestinal; BOR, best objective response; NR, no response; R, response; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; MR, mixed response; TIDE, tumor immune dysfunction and exclusion; MDSC, myeloid-derived suppressor cell; CAF, cancer-associated fibroblast; TAM, tumor-associated macrophage; APM, antigen-presenting machinery.