Updates on intratumoral therapies in melanoma

Abstract

Intratumoral therapies provide an opportunity for novel strategies in the management of advanced melanoma. These approaches deliver concentrated doses of therapeutic immune agents directly into individual tumor(s), achieving local tumor control and induction of systemic antitumor immune responses while minimizing the risk of immune‐related adverse events. Talimogene laherparepvec, a genetically modified herpes simplex virus type 1–encoding granulocyte‐macrophage colony–stimulating factor, was the first oncolytic viral therapy approved in a solid tumor indication. In pivotal trials of patients with melanoma, talimogene laherparepvec demonstrated durable responses. Building on this paradigm, next‐generation oncolytic agents incorporate additional genetic modifications, such as fusogenic proteins and immunostimulatory transgenes, to enhance local cytotoxicity and systemic immune priming. Clinical studies of intratumoral, injectable agents since 2010 have evaluated monotherapy as well as combination strategies with immune checkpoint inhibitors, revealing improved response rates and durable remissions, including in patients with immune checkpoint inhibitor‐resistant disease. This review summarizes the mechanistic rationale, preclinical evidence, and clinical development of intratumoral therapies in melanoma. Key trial outcomes, safety profiles, and practical considerations for administration are discussed. Emerging trends include image‐guided visceral injection, combinatorial regimens, and the integration of intratumoral therapy in the neoadjuvant setting. As these therapies evolve, intratumoral approaches may expand their role in melanoma management, bridging locoregional tumor control with systemic immune activation and complementing existing systemic treatments.