Integrated analysis of stemness-associated immune modulatory circuits in squamous cell carcinomas

Guo, W.; Leon, D.; Luan, J.; Gang, A.; Huang, X.; Nicholson, B.; Dorosz, K.; Zhao, Y. S.; Grimshaw, S.; Bolotin, D.; Lingen, M. W.; Vokes, E. E.; Pearson, A.; Rosenberg, A. J.; Shen, L.; Izumchenko, E.; Agrawal, N.; Jiang, J.; Miao, Y. P.

doi:10.64898/2026.04.02.716182

bioRxiv · 10.64898/2026.04.02.716182

Integrated analysis of stemness-associated immune modulatory circuits in squamous cell carcinomas

Guo, W.·Leon, D.·Luan, J.·Gang, A.·Huang, X.·Nicholson, B.·Dorosz, K.·Zhao, Y. S.·Grimshaw, S.·Bolotin, D.·Lingen, M. W.·Vokes, E. E.·Pearson, A.·Rosenberg, A. J.·Shen, L.·Izumchenko, E.·Agrawal, N.·Jiang, J.·Miao, Y. P.

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Abstract

Emerging evidence indicates that a subset of cancer cells enriched for stemness-related gene signatures possess distinct immunomodulatory capacities, enabling these tumor-initiating stem cells (tSCs) to more effectively evade or resist anti-tumor immunity. Despite these advances, the tSC-specific molecular circuits orchestrating their specialized immune privilege program are not well defined. Here, in squamous cell carcinomas of the skin and oral cavity, we comprehensively delineate the unique immune-evasive properties of tSCs and dissect the transcriptional regulation shaping their immunomodulatory programs. By integrating transcriptome profiling, chromatin landscape mapping, genetic perturbation, and single-cell RNA sequencing, we found that the tSC-specific immune program is broadly governed by SOX2, a stemness-associated transcription factor. We demonstrate that SOX2 enables tSCs to sustain immature tumor-associated neutrophils (TANs) and subsequently trigger these myeloid cells to foster the development of tumor-associated macrophages (TAMs). This SOX2-directed tSC-TAN-TAM axis establishes a localized immunosuppressive niche for protecting tSC. SIGNIFICANCEHere, we uncover SOX2 as a master regulator that orchestrates conserved immune modulatory circuits in tSCs to sustain pro-tumor myeloid cell states. These findings place tSCs at the apex of immune landscape remodeling, asserting a central role of stemness-associated program in organizing the immunosuppressive tumor microenvironment.

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Guo, W., Leon, D., Luan, J., Gang, A., Huang, X., Nicholson, B., Dorosz, K., Zhao, Y. S., Grimshaw, S., Bolotin, D., Lingen, M. W., Vokes, E. E., Pearson, A., Rosenberg, A. J., Shen, L., Izumchenko, E., Agrawal, N., Jiang, J., Miao, Y. P.. 2026-04-06. Integrated analysis of stemness-associated immune modulatory circuits in squamous cell carcinomas. https://doi.org/10.64898/2026.04.02.716182

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