Autophagy meets tissue-resident memory: Emerging crosstalk and therapeutic opportunities in cutaneous melanoma

Melanoma is a highly immunogenic human cancer characterized by complex immune responses within the tumor microenvironment (TME). Among these, tumor-infiltrating lymphocytes (TILs) and tissue-resident memory T cells (TRM) are strongly associated with favorable prognosis and response to immune checkpoint blockade, reflecting their central role in sustaining anti-tumor immunity. Emerging evidence suggests that the activity and persistence of these T cell subsets are critically influenced by autophagy, a cellular process that maintains metabolic fitness, prevents exhaustion, and supports effector functions under nutrient-limited and stressful conditions typical of the TME. Understanding the autophagy-T cell axis may open new avenues for therapeutic strategies aimed at enhancing melanoma immunosurveillance and improving patient outcomes. In this review, we explore the intersection between TRM-cell biology and autophagy in cutaneous melanoma, outlining TRM differentiation and functions in the tumor setting, reviewing autophagy within melanoma cells, and examining evidence for their potential crosstalk. We further discuss how autophagy may shape TRM development, maintenance, and function, while tumor-intrinsic autophagy modulates TIL and TRM-mediated responses, and conclude by highlighting therapeutic opportunities, including those under investigation in registered clinical trials. By providing insights into this intricate interplay, the review aims to stimulate further investigation and support the development of targeted TRM-based therapeutic strategies for melanoma.