The Frontier of Melanoma Treatment: Defeating Immunotherapy Resistance—A Systematic Review

Objectives: Immunotherapy based on immune checkpoint blockade (ICB) has become a key treatment for melanoma. However, the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop methods to overcome this resistance. This study aims to collect the most recent information on melanoma immunotherapy, discuss potential strategies to overcome resistance to immunotherapy, and identify areas that require further analysis. Methods: To achieve this goal, scientific publications from 2021-2024 available in PubMed and Google Scholar databases were analyzed. The databases were searched using the following terms: "melanoma", "immunotherapy", "Immune Checkpoint Blockade", and "immunoresistance". Results: The results of preclinical and early-stage clinical research indicate the potential application of tank-binding kinase 1 (TBK-1), fecal microbiota transplant (FMT), Toll-like Receptor 9 (TLR9), lipid nanoparticles (LNPs) containing a stimulator of an interferon gene agonist (STING), BRAF inhibitors, Lymphocyte Activation Gene (LAG-3), T-Cell Immunoglobulin and ITIM Domain (TIGIT), and oncolytic viruses (OVs) as potential methods to enhance melanoma sensitivity to ICB. Discussion: To optimize immunotherapy, further research is needed to determine the detailed mechanisms of action, safety profiles, tolerability, and precise patient selection criteria for methods capable of overcoming melanoma's immunoresistance.