CONCEPT PROPOSAL: COMBINATION THERAPY FOR MELANOMA — INTRATUMORAL PRIME EDITING, DUAL CHECKPOINT BLOCKADE, AND IN SITU ABLATIVE IMMUNIZATION

Advanced cutaneous melanoma remains difficult to treat once disease spreads beyond the primary lesion. This concept proposal combines three existing approaches into a single sequence: (1) intratumoral prime editing delivered by lipid nanoparticles (LNPs) to rewrite oncogenic driver sequences or disrupt immunosuppressive loci without double-strand DNA breaks; (2) systemic dual PD-1/CTLA-4 checkpoint blockade to expand the stem-like T-cell pool; and (3) local tumor ablation to release tumor antigens and damage-associated molecular patterns, driving systemic T-cell priming against distant, untreated metastases (the abscopal effect). The proposed preclinical test is a bilateral B16F10 melanoma model in C57BL/6 mice, with editing efficiency measured by next-generation sequencing, immune profiling by flow cytometry and single-cell RNA sequencing, and bilateral tumor kinetics and survival as endpoints. All expectations are stated as predictions to be tested, not results: no data were generated and no experiments were performed. To the author's knowledge, this specific three-part combination has not been published or tested together.