<p>While immunotherapy has been widely adopted for the treatment of melanoma, its application in patients with complex comorbidities remains challenging. This review explores evidence on the efficacy, safety, and special considerations for the use of immunotherapy in patients with altered immune systems, including patients with human immunodeficiency virus (HIV), tuberculosis, solid organ or hematopoietic cell transplantation, autoimmune diseases, and pregnant women. Despite data emphasizing the feasibility of immunotherapy treatment in these populations, standardized management algorithms are lacking. Future research should consider either including these patients in prospective trials or attempting to collect data via registries to provide more clarity on the management of immunologically vulnerable patients with melanoma.</p>