CD70 drives cSCC growth by linking DNA damage response, inflammation, and tumor-stromal signaling.

Chronic ultraviolet (UV) exposure drives the development of non-melanoma skin cancers (NMSCs), particularly cutaneous squamous cell carcinoma (cSCC), through persistent DNA damage and inflammation. However, the molecular mediators that link genotoxic stress to tumor-promoting signaling and stromal activation remain poorly defined. Here, we identify CD70, a TNF superfamily member, as a UV- and DNA damage-inducible regulator that coordinates epithelial and stromal responses to promote skin carcinogenesis. Integrative analyses of transcriptomic (GTEx, GSE2503, GSE42677), proteomic (RPPA), and immunostaining datasets revealed marked upregulation of CD70 in sun-exposed skin, actinic keratoses, and cSCC lesions. Functionally, CD70 silencing suppressed cSCC proliferation and xenograft growth, whereas solar UV or DMBA exposure induced CD70 expression. Mechanistically, E2F1 directly bound and activated the CD70 promoter, establishing a transcriptional axis linking the DNA damage response to CD70 upregulation. CD70 depletion disrupted cytokine-receptor and MAPK/NF-κB signaling and altered inflammatory gene expression in UV-irradiated keratinocytes. In dermal fibroblasts, TGF-β-induced CD70 enhanced NF-κB activation and secretion of IL-6 and MCP3, thereby reinforcing paracrine inflammatory loops that supported cSCC spheroid expansion and tumor progression. CD70 knockdown in fibroblasts abrogated these effects and reduced tumor proliferation and cytokine expression in vivo. Collectively, our findings identify CD70 as a stress-inducible signaling hub that links DNA damage, inflammation, and tumor-stromal communication in skin carcinogenesis. Targeting CD70 may disrupt this feed-forward inflammatory circuit and provide a therapeutic strategy for inflammation-driven skin cancer.