The immune landscape of primary melanoma: prognostic insights in the era of spatial biology and early immunotherapy

Immune checkpoint inhibitors (ICI), including anti-PD-1 and anti-CTLA-4, have greatly improved survival rates in patients with advanced melanoma. Recently, clinical trials have demonstrated the efficacy of ICIs in extending recurrence-free survival in patients diagnosed with high-risk localised primary melanoma (stage IIB/IIC). Still, a significant proportion of stage IIB/IIC melanoma patients will not recur if untreated, risking overtreatment and exposure to toxicities. This highlights the need for accurate prognostication of risk of metastasis in patients with localised melanoma at diagnosis to identify those truly at risk that will benefit from ICI therapy. In this review, we describe prognostic implications of immune populations and immune cell structures in primary melanoma, the evidence available for their metastatic potential in early-stage disease, as well as recent developments in spatial proteomics and transcriptomics that are generating new knowledge in the primary melanoma setting. Future research will benefit from incorporating cost-effective approaches to spatial analysis of specimens with these technologies across melanoma subtypes, including rarer types such as acral and mucosal disease that frequently don’t respond to ICI.