Peripheral glia drive the initiation of cutaneous squamous cell carcinoma

Although tumor innervation is known to promote cancer progression, underlying mechanisms remain poorly understood and have mostly been linked to axonal signaling. Here, we identify peripheral glia as critical drivers of cutaneous squamous cell carcinoma (cSCC), the second most common skin cancer in humans. Tumor-associated glial cells (TAGs) resemble embryonic Schwann cell lineage stages, are abundant in the stroma of premalignant lesions and established murine and human cSCC, and are essential for tumor formation. TAG activation in premalignant lesions is triggered by UV-induced anti-inflammatory macrophages, which in turn are polarized by TAGs into pro-tumorigenic FcεRIα⁺ macrophages, key components of the cSCC microenvironment. Consequently, TAG depletion reduces FcεRIα⁺ macrophages, cancer-associated fibroblasts, and epithelial-mesenchymal transition in keratinocytes, thereby impairing cSCC initiation by disrupting intercellular communication required for tumor development. As most solid tumors are innervated and harbor peripheral glia, our findings reveal TAGs as previously unrecognized regulators of tumor initiation with relevance beyond skin cancer.