KEY POINTS
- Acral melanoma differs substantially from UV-driven cutaneous melanoma. It typically has lower tumor mutational burden, fewer neoantigens, greater structural genomic instability and a more immunosuppressive tumor microenvironment with fewer cytotoxic CD8⁺ cells and more exhausted and regulatory T-cell populations.
- BRAF mutations, dominant in conventional cutaneous melanoma, occur in only approximately 10–20% of acral melanomas. KIT, NRAS and structural alterations are more prominent; KIT mutations or amplifications involving exons 11 and 13 occur in up to one-third of cases.
- These biological differences appear clinically relevant to immunotherapy. The review cites PD-L1 expression of approximately 31% in acral versus 62% in non-acral cutaneous melanoma, while advanced acral melanoma series report median overall survival around 15 months with dual checkpoint blockade and approximately 18 months with anti-PD-1 monotherapy.
- RT could theoretically convert this immune-cold phenotype through immunogenic cell death, tumor-antigen release, dendritic-cell activation and cGAS-STING signaling, potentially expanding the TCF1⁺PD-1⁺ progenitor-exhausted CD8⁺ T-cell reservoir that supports sustained checkpoint-inhibitor responses.
- Fractionation may matter. Very high single doses can induce TREX1 at approximately 12–18 Gy per fraction, degrading cytosolic DNA and potentially attenuating cGAS-STING signaling. The authors therefore argue that moderately hypofractionated RT may offer a more favorable immunologic profile than very high single-fraction doses.
- The review also highlights preservation of tumor-draining lymph nodes as a potentially important component of immuno-radiotherapy, because they contain dendritic-cell and progenitor T-cell populations involved in systemic antitumor immune responses.
- No randomized trial has established the optimal RT dose, fractionation or sequencing with checkpoint inhibition specifically in acral melanoma. Mechanistic data favor RT-first immune priming, whereas some clinical observations have suggested ICI followed by RT; neither strategy currently has comparative clinical evidence.
CLINICAL TAKEAWAY
Acral melanoma should not simply be viewed as cutaneous melanoma arising at a different anatomical site. Its lower antigenicity and immune-excluded biology provide a strong rationale for RT-based immune priming, but this remains a translational hypothesis rather than an established treatment strategy.