Abstract Immune evasion is a hall mark of cancer, but whether every tumor cell employs similar mechanisms to escape immune surveillance is still under debate. Recent studies pointed to a subset of cancer cells that are enriched with stemness related gene signatures can activate unique immune modulatory program, allowing these tumor initiating stem cells (tSCs) to better evade or resist anti-tumor immunity. However, the tSC specific molecular circuit that orchestrate their specialized immune privilege program remains undefined. Here, we compared the transcriptome of various tumor cell populations isolated from squamous cell carcinomas (SCCs) derived from different tissues. This comprehensive profiling defined distinct immune evasive properties of tSCs. Combining this analysis with chromatin landscape mapping, genetic perturbation, and single cell RNA-sequencing, we identified that the TIC-specific immune modulatory program is broadly regulated by SOX2, a stemness-associated transcription factor. Delving into the mechanism, we first found that SOX2 upregulates fatty acid desaturase 1 (Fads1) to produce arachidonic acid (AA). This tSC specific pathway enhances the prostaglandin E2 (PGE2) signaling in tumor-associated neutrophils (TANs), which can disrupt the interferon response and prevent the interferon induced anti tumor functions in TANs. In addition, SOX2 also promotes tSCs to produce CSF3, facilitating the immature TANs to secrete CSF1, supporting the development of CD206+ tumor-associated macrophages (TAMs). This tSCs TAN TAM crosstalk orchestrated by SOX2 then sculpts a localized immune suppressive niche that protect tSCs. This study uncovers SOX2 functions as the master regulator that governs the conserved stemness-associated immune modulatory circuits to endow the tSCs with enhanced ability to sustain the pro-tumor and immune suppressive cell states of myeloid cells. These findings placed tSCs at the apex position where they instruct the organization of the immune suppressive tumor microenvironment. Citation Format: Yuxuan Miao. Dissecting stemness associated molecular circuits that shape the immune suppressive tumor microenvironment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB311.
Yuxuan Miao (Fri,) studied this question.