The gut-skin axis in melanoma: from microbial regulatory mechanisms to clinical translation for precision management.

Melanoma is an aggressive cutaneous malignancy with poor prognosis in advanced stages. Immune checkpoint inhibitors (ICIs) act as first-line therapy, yet are limited by primary/acquired resistance and immune-related adverse events (irAEs). The gut-skin axis, which links gut and skin microbiota to host physiology, has been increasingly implicated in melanoma tumorigenesis, progression and therapeutic efficacy, while its systemic mechanisms and clinical value remain incompletely understood. In this review, the multi-dimensional regulation of melanoma via the gut-skin axis is dissected through six core axes, namely immune regulation, metabolism-tumor microenvironment, aging-inflammaging, endocrine, circadian rhythm and ultraviolet (UV) radiation. Mechanism-driven microbiota-host interaction biomarkers (MHIBs) are proposed as a hypothesis-generating framework, which differ from conventional biomarkers in aiming to capture functional microbiota-host crosstalk. Six microbiota-targeted intervention strategies and their potential synergistic effects with mainstream therapies including ICIs, targeted therapy, chemotherapy and radiotherapy are summarized alongside critical translational barriers, and a multi-omics-based framework for functional microbiota stratification is proposed. Notably, bidirectional gut-skin microbiota crosstalk is highlighted to conceptualize a working model of the "microbiota-gut-skin axis-melanoma" relationship, broadening the one-sided focus on gut microbiota. Key challenges in this field are addressed, including unclear causal relationships, lack of standardized research protocols and insufficient clinical evidence. Corresponding future research priorities are put forward for mechanistic validation, biomarker clinical translation and personalized intervention development, which provide novel insights for the precision diagnosis and treatment of melanoma.