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Overcoming Resistance Mechanisms to Melanoma Immunotherapy

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Abstract

The advent of immune checkpoint inhibition has revolutionized treatment of advanced melanoma. While most patients derive survival benefit from established immunotherapies, notably monoclonal antibodies blocking cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1, a subset does not optimally respond due to the manifestation of innate or acquired resistance to these therapies. Combination regimens have proven efficacious relative to single-agent blockade, but also yield high-grade treatment toxicities that are often dose-limiting for patients. In this review, we discuss the significant strides made in the past half-decade toward expanding the melanoma immunotherapy treatment paradigm. These include newly approved therapies, adoption of neoadjuvant immunotherapy, and studies in the clinical trials pipeline targeting alternative immune checkpoints and key immunoregulatory molecules. We then review how developments in molecular and functional diagnostics have furthered our understanding of the tumor-intrinsic and -extrinsic mechanisms driving immunotherapy resistance, as well as highlight novel biomarkers for predicting treatment response. Throughout, we discuss potential approaches for targeting these resistance mechanisms in rational combination with established immunotherapies to improve outcomes for patients with melanoma.

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Authors and Affiliations

  1. Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    David X. Zheng, David J. Bozym, Ryan J. Sullivan & Russell W. Jenkins

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Giuseppe Tarantino & David Liu

  3. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    David Liu & Russell W. Jenkins

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  1. David X. Zheng
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  2. David J. Bozym
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  3. Giuseppe Tarantino
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  5. David Liu
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  6. Russell W. Jenkins
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Correspondence to Russell W. Jenkins.

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Funding

This paper was supported by the grant National Institutes of Health R38AG070229 to David X. Zheng.

Conflicts of Interest

Russell W. Jenkins is a member of the advisory board for and has a financial interest in Xsphera Biosciences Inc., a company focused on using ex vivo profiling technology to deliver functional, precision immune-oncology solutions for patients, providers, and drug development companies. Russell W. Jenkins has received honoraria from Incyte (invited speaker), G1 Therapeutics (advisory board), and Bioxcel Therapeutics (invited speaker). Russell W. Jenkins has ownership interest in US patents US20200399573A9 and US20210363595A1. Russell W. Jenkins’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. Ryan J. Sullivan has served as a consultant or on an advisory board for BMS, Merck, Pfizer, Marengo, and Replimune, and has received research funding from Merck. David X. Zheng, David J. Bozym, Giuseppe Tarantino, and David Liu declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

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Availability of Data and Material

No datasets were generated or analyzed during the current study.

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Authors’ Contributions

D.X.Z.: conceptualization, writing—original draft preparation, project administration, and funding acquisition. D.J.B.: conceptualization and writing—original draft preparation. G.T.: conceptualization, writing—original draft preparation, and visualization. R.J.S.: conceptualization, writing—reviewing and editing, and supervision. D.L.: conceptualization and writing—reviewing and editing, and supervision. R.W.J.: conceptualization, writing—reviewing and editing, supervision, and project administration.

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Zheng, D.X., Bozym, D.J., Tarantino, G. et al. Overcoming Resistance Mechanisms to Melanoma Immunotherapy. Am J Clin Dermatol 26, 77–96 (2025). https://doi.org/10.1007/s40257-024-00907-7

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