Cornification represents a specialized epidermal differentiation program that evolved in amniotes, facilitating adaptation to a fully terrestrial lifestyle. Despite the significant genotoxic stress imposed by ultraviolet (UV) B radiation on the skin, chronic exposure compromises T cell-mediated immunity, leading to tumorigenesis. Loricrin, an essential component of the cornified cell envelope, exhibits superior polymerizing capacity, conferring protection against oxidative stressors, including UVB radiation. Previous studies have demonstrated that loricrin knockout (LKO) mice exhibit heightened susceptibility to sunburn. To elucidate the role of loricrin in UVB-induced tumorigenesis, we compared LKO mice to wild type (WT) controls. Unexpectedly, LKO mice displayed relative resistance to photocarcinogenesis, as evidenced by increased tumor-free survival rates (p < 0.05) and a threefold reduction in tumor burden (p < 0.0001). Following full-thickness wounding, LKO mice exhibited over a twofold increase in epithelialization (p < 0.0001) and wound closure rates (p < 0.0001) compared to WT mice. However, their reparative capacity post-UVB irradiation, which depends on skin regulatory T cells, was not enhanced relative to WT mice. Notably, antibody-mediated CD25 blockade impaired wound healing but restored the UVB-induced pro-healing effect in LKO mice. Furthermore, our observations revealed a morphological signature of T cell receptor activation in naive LKO epidermis, characterized by increased CD3/F-actin-rich aggregates (p < 0.001). These findings implicate loricrin as a pivotal regulator of T cell responses in the skin, unveiling previously unrecognized functions of the cornified cell envelope.