Abstract Chronic ultraviolet (UV) exposure is a key driver of cutaneous squamous cell carcinoma (cSCC), yet the molecular mechanisms connecting genotoxic stress to tumor–stromal signaling remain unclear. Here, we identify CD70, a TNF superfamily member, as a UV- and DNA damage–inducible regulator that coordinates communication between cSCC cells and fibroblasts. At the expression level, integrative transcriptomic, proteomic, and histological analyses revealed strong CD70 induction in sun-exposed skin, actinic keratoses, and cSCC tissues. At the functional level, silencing CD70 suppressed cSCC proliferation and xenograft tumor growth, whereas solar UV or DMBA exposure markedly elevated its expression. Mechanistically, E2F1 directly bound and activated the CD70 promoter, establishing a transcriptional link between the DNA damage response and CD70 induction. Loss of CD70 attenuated MAPK/NF-κB signaling and reduced inflammatory gene expression in UV-irradiated keratinocytes. In dermal fibroblasts, CD70 expression enhanced NF-κB activation and secretion of IL-6 and MCP3, amplifying paracrine inflammatory loops that promoted cSCC spheroid expansion and tumor progression. Together, these findings define CD70 as a stress-responsive signaling hub that integrates DNA damage, cell proliferation, and epithelial–stromal communication to drive skin carcinogenesis. Targeting CD70 may disrupt this pro-inflammatory circuit and offer a novel therapeutic strategy for inflammation-associated skin cancer. Citation Format: Qiushi Wang, Asad U. Khan, Chengcheng Hu, Emanuel F. Petricoin, Rebecca Morris, Sally Dickinson, Georg T. Wondrak, Ann M. Bode, Clara Curiel-Lewandrowski, Tianshun Zhang. CD70 Links DNA Damage, Proliferation, and Tumor–Stromal Communication abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B028.
Wang et al. (Wed,) studied this question.