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The tumor microenvironment (TME) subtype is a critical factor when combining immunotherapy with tumor debulking strategies such as ultrasound ablation. To understand the effects of the TME subtype, we studied two multi-site murine cancer models, an immune-suppressed KPC (Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre) pancreatic adenocarcinoma (MT4) model and a neu deletion HER2+ (NDL) mammary adenocarcinoma model with a larger naïve lymphocyte population. After profiling the two models with histology and single-cell sequencing, we designed immunotherapy combinations with Magnetic Resonance-guided Focused Ultrasound (MRgFUS) thermal ablation that were specific to each TME subtype. To understand the impact of the molecular and cellular differences upon each model, we characterized the treatment effect with transcriptomic analysis and digital cytometry. We found that combining MRgFUS ablation with immunotherapy reduced tumor growth and extended survival by at least 2-fold in the MT4 pancreatic cancer model. Gene set enrichment analysis (GSEA) of bulk RNA sequencing data indicated that the combination of ablation with immunotherapy preferentially enriched functional annotations for leukocyte migration in the MT4 model and wound healing and inflammatory cytokines in the NDL model (e.g. for IL6: 1.6 fold increase in MT4 vs 10.3 fold in NDL tumors). We then particularly focused on whether dendritic cell (DC) activation and CD4 T cell populations could be enhanced when ablating pancreatic tumors. By CIBERSORTx digital cytometry, aCD40 + aPD-1 combinations increased the presence of activated DCs in MT4 tumors by 2.4-fold. Activated DCs were also increased by CP4 (aCD40 + aPD-1 + CTLA-4) alone 1.7 fold or in combination with ablation in both treated (2.4 fold) and distant (2.2 fold) lesions. Ablation combined with aPD-1 alone did not significantly impact DCs in the MT4 model. In addition, CD4 lymphocytes increased 5 and 8 fold in treated and distant tumors by ablation combined with CP4 in the MT4 model. Taken together, inflammatory cytokines were preferentially elevated by ablation in a dense epithelial breast cancer as compared with a pancreatic tumor model. Further, the results suggest that aCD40 immunotherapy retains efficacy when combined with thermal ablation in pancreatic tumors. This work can inform clinical translation of ablative and immunotherapy combination protocols. Citation Format: James Wang, Brett Z. Fite, Aris Kare, Bo Wu, Marina N. Raie, Spencer Tumbale, Ryan R. Davis, Clifford G. Tepper, Katherine Ferrara. TME subtype impacts response to combined thermal ablation and immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6314.