Immunotherapy in melanoma: advances, pitfalls, and future perspectives

Abstract

Cutaneous melanoma is the deadliest and most aggressive form of skin cancer owing to its high capacity for metastasis. Over the past few decades, the management of this type of malignancy has undergone a significant revolution with the advent of both targeted therapies and immunotherapy, which have greatly improved patient quality of life and survival. Nevertheless, the response rates are still unsatisfactory for the presence of side effects and development of resistance mechanisms. In this context, tumor microenvironment has emerged as a factor affecting the responsiveness and efficacy of immunotherapy, and the study of its interplay with the immune system has offered new promising clinical strategies. This review provides a brief overview of the currently available immunotherapeutic strategies for melanoma treatment by analyzing both the positive aspects and those that require further improvement. Indeed, a better understanding of the mechanisms involved in the immune evasion of melanoma cells, with particular attention on the role of the tumor microenvironment, could provide the basis for improving current therapies and identifying new predictive biomarkers.

Keywords: adoptive cell therapy (ACT); immune checkpoint inhibitors (ICIs); immunotherapy; melanoma; precision medicine.

FIGURE 1

Schematic representation of the most important ICI blockades in melanoma. Under normal conditions, T cell activation is provided by the MHC and TCR signaling pathways, while these pathways are suppressed by the ICIs working together in the tumor microenvironment. ICIs block the interactions between checkpoints and their partner proteins, thus preventing the off signals from being sent, consequently allowing the T cells to kill the cancer cells. This image was created with BioRender (https://biorender.com).

FIGURE 2

Alternative immunotherapy approaches in melanoma. Although still evolving, alternative immunotherapeutic approaches to ICIs are gaining ground in the treatment of several tumor types, such as metastatic melanoma. This image was created with BioRender (https://biorender.com).