UVB Effect on Melanoma Patient Response to Immunotherapy
Main Article Content
Abstract
Ultraviolet B (UVB) radiation is a primary driver of cutaneous melanoma and a major contributor to its high tumor mutational burden. Classically, this mutational load generates neo-antigens that generally correlate with a favorable response to immune checkpoint inhibitors. However, melanomas arising in chronically sun-damaged skin frequently exhibit therapeutic resistance. This review proposes to uncouple the beneficial effect of UVB-induced neo-antigens from the broader consequences of UVB exposure that may also promote treatment resistance. Identifying these specific UV-induced factors provides a framework to better predict immunotherapy failure in high tumor mutational burden patients and highlights novel therapeutic targets.
Article Details
How to Cite
MALIAH, Avishai; LEVY, Carmit; FISHER, David E..
UVB Effect on Melanoma Patient Response to Immunotherapy.
Medical Research Archives, [S.l.], v. 14, n. 4, apr. 2026.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/7365>. Date accessed: 01 may 2026.
doi: https://doi.org/10.18103/mra.v14i4.7365.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49.
2. Agar NS, Halliday GM, Barnetson RS, et al. The basal layer in human squamous tumors harbors more UVA than UVB fingerprint mutations: a role for UVA in human skin carcinogenesis. Proc Natl Acad Sci U S A. 2004;101(14):4954-4959.
3. Courdavault S, Baudouin C, Charveron M, et al. Repair of the three main types of bipyrimidine DNA photoproducts in human keratinocytes exposed to UVB and UVA radiations. DNA Repair (Amst). 2005;4(7):836-844.
4. Sha X, Vartanian V, Owen N, et al. Modulation of UVB-induced Carcinogenesis by Activation of Alternative DNA Repair Pathways. Sci Rep. 2018;8:1-11.
5. Van Allen EM, Miao D, Schilling B, et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science. 2015;350(6257):207-211.
6. Trucco LD, Mundra PA, Hogan K, et al. Ultraviolet radiation-induced DNA damage is prognostic for outcome in melanoma. Nat Med. 2019;25(2):221-224.
7. Fell GL, Robinson KC, Mao J, et al. Skin β-endorphin mediates addiction to UV light. Cell. 2014;157(7):1527-1534.
8. Bald T, Quast T, Landsberg J, et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature. 2014;507(7490):109-113.
9. Riaz N, Havel JJ, Makarov V, et al. Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab. Cell. 2017;171(4):934-949.e16.
10. Lo JA, Kawakubo M, Juneja VR, et al. Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses. Sci Transl Med. 2021;13(581):eabd8636.
11. Shoushtari AN, Chatila WK, Arora A, et al. Therapeutic Implications of Detecting MAPK-Activating Alterations in Cutaneous and Unknown Primary Melanomas. Clin Cancer Res. 2021;27(8):2226-2235.
12. Fadaki N, Li R, Parrett B, et al. Solar elastosis is a predictor of survival in patients with melanoma. BMC Cancer. 2013;13:175.
13. Callender GG, Egger ME, Burton AL, et al. Prognostic implications of anatomic location of primary cutaneous melanoma of 1 mm or thicker. Am J Surg. 2011;202(6):659-664.
14. Hoersch B, Leiter U, Garbe C. Is head and neck melanoma a distinct entity? A clinical registry-based comparative study in 5702 patients with melanoma. Br J Dermatol. 2006;155(4):771-777.
15. Hayward NK, Wilmott JS, Waddell N, et al. Whole-genome landscapes of major melanoma subtypes. Nature. 2017;545(7653):175-180.
16. Wolf Y, Bartok O, Patkar S, et al. UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma. Cell. 2019;179(1):219-235.e21.
17. McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351(6280):1463-1469.
18. Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. N Engl J Med. 2016;375(9):819-829.
19. Fischer F, Janel N, Hoppe P, et al. Warburg effect in melanoma: A key to therapy resistance. Pigment Cell Melanoma Res. 2007;20(6):448-456.
20. Chang CH, Qiu J, O'Sullivan D, et al. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell. 2015;162(6):1229-1241.
21. Benci JL, Xu B, Qiu Y, et al. Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade. Cell. 2016;167(6):1540-1554.e12.
22. D'Orazio JA, Nobuhisa T, Cui R, et al. Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning. Nature. 2006;443(7109):340-344.
23. Cui R, Widlund HR, Feige E, et al. Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell. 2007;128(5):853-864.
24. Carreira S, Goodall J, Denat L, et al. Mitf regulation of Dia1 controls melanoma proliferation and invasiveness. Genes Dev. 2006;20(24):3426-3439.
25. Kawakami A, Fisher DE. The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology. Lab Invest. 2017;97(6):649-656.
26. Elkoshi N, Parikh S, Malcov-Brog H, et al. Ataxia Telangiectasia Mutated Signaling Delays Skin Pigmentation upon UV Exposure by Mediating MITF Function toward DNA Repair Mode. J Invest Dermatol. 2023;143(12):2494-2506.e4.
27. Hugo W, Zaretsky JM, Sun L, et al. Genomic and Transcriptomic Features of Response to Anti-PD-1 Blockade in Melanoma. Cell. 2016;165(1):35-44.
28. Premi S, Wallisch S, Mano CM, et al. Photochemistry. Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure. Science. 2015;347(6224):842-847.
29. Chemla Y, et al. HLA export by melanoma cells decoys cytotoxic T cells to promote immune evasion. Cell. 2025.
30. González Maglio DH, Paz ML, Leoni J. Sunlight Effects on Immune System: Is There Something Else in addition to UV-Induced Immunosuppression? Biomed Res Int. 2016;2016:1934518.
31. Schade N, Esser C, Krutmann J. Ultraviolet B radiation-induced immunosuppression: Molecular mechanisms and cellular alterations. Photochem Photobiol Sci. 2005;4(9):699-708.
32. Schwarz T. Mechanisms of UV-induced immunosuppression. Keio J Med. 2005;54(4):165-171.
33. Jessup JM, Hanna N, Palaszynski E, Kripke ML. Mechanisms of depressed reactivity to dinitrochlorobenzene and ultraviolet-induced tumors during ultraviolet carcinogenesis in BALB/c mice. Cell Immunol. 1978;38(1):105-115.
34. Denkins Y, Fidler IJ, Kripke ML. Exposure of mice to UV-B radiation suppresses delayed hypersensitivity to Candida albicans. Photochem Photobiol. 1989;49(5):615-619.
35. Howie S, Norval M, Maingay J. Exposure to low-dose ultraviolet radiation suppresses delayed-type hypersensitivity to herpes simplex virus in mice. J Invest Dermatol. 1986;86(2):125-128.
36. Jeevan A, Kripke ML. Effect of a single exposure to ultraviolet radiation on Mycobacterium bovis bacillus Calmette-Guerin infection in mice. J Immunol. 1989;143(9):2837-2843.
37. Romerdahl CA, Donawho C, Fidler IJ, Kripke ML. Effect of ultraviolet-B radiation on the in vivo growth of murine melanoma cells. Cancer Res. 1988;48(14):4007-4010.
38. Maliah A, et al. Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy. Nat Commun. 2024.
39. Maliah A, et al. Systemic effect of ultraviolet radiation on lung cancer growth. Sci Rep. 2026.
40. Kaur A, Webster MR, Marchbank K, et al. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature. 2016;532(7598):250-254.
2. Agar NS, Halliday GM, Barnetson RS, et al. The basal layer in human squamous tumors harbors more UVA than UVB fingerprint mutations: a role for UVA in human skin carcinogenesis. Proc Natl Acad Sci U S A. 2004;101(14):4954-4959.
3. Courdavault S, Baudouin C, Charveron M, et al. Repair of the three main types of bipyrimidine DNA photoproducts in human keratinocytes exposed to UVB and UVA radiations. DNA Repair (Amst). 2005;4(7):836-844.
4. Sha X, Vartanian V, Owen N, et al. Modulation of UVB-induced Carcinogenesis by Activation of Alternative DNA Repair Pathways. Sci Rep. 2018;8:1-11.
5. Van Allen EM, Miao D, Schilling B, et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science. 2015;350(6257):207-211.
6. Trucco LD, Mundra PA, Hogan K, et al. Ultraviolet radiation-induced DNA damage is prognostic for outcome in melanoma. Nat Med. 2019;25(2):221-224.
7. Fell GL, Robinson KC, Mao J, et al. Skin β-endorphin mediates addiction to UV light. Cell. 2014;157(7):1527-1534.
8. Bald T, Quast T, Landsberg J, et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature. 2014;507(7490):109-113.
9. Riaz N, Havel JJ, Makarov V, et al. Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab. Cell. 2017;171(4):934-949.e16.
10. Lo JA, Kawakubo M, Juneja VR, et al. Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses. Sci Transl Med. 2021;13(581):eabd8636.
11. Shoushtari AN, Chatila WK, Arora A, et al. Therapeutic Implications of Detecting MAPK-Activating Alterations in Cutaneous and Unknown Primary Melanomas. Clin Cancer Res. 2021;27(8):2226-2235.
12. Fadaki N, Li R, Parrett B, et al. Solar elastosis is a predictor of survival in patients with melanoma. BMC Cancer. 2013;13:175.
13. Callender GG, Egger ME, Burton AL, et al. Prognostic implications of anatomic location of primary cutaneous melanoma of 1 mm or thicker. Am J Surg. 2011;202(6):659-664.
14. Hoersch B, Leiter U, Garbe C. Is head and neck melanoma a distinct entity? A clinical registry-based comparative study in 5702 patients with melanoma. Br J Dermatol. 2006;155(4):771-777.
15. Hayward NK, Wilmott JS, Waddell N, et al. Whole-genome landscapes of major melanoma subtypes. Nature. 2017;545(7653):175-180.
16. Wolf Y, Bartok O, Patkar S, et al. UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma. Cell. 2019;179(1):219-235.e21.
17. McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351(6280):1463-1469.
18. Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. N Engl J Med. 2016;375(9):819-829.
19. Fischer F, Janel N, Hoppe P, et al. Warburg effect in melanoma: A key to therapy resistance. Pigment Cell Melanoma Res. 2007;20(6):448-456.
20. Chang CH, Qiu J, O'Sullivan D, et al. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell. 2015;162(6):1229-1241.
21. Benci JL, Xu B, Qiu Y, et al. Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade. Cell. 2016;167(6):1540-1554.e12.
22. D'Orazio JA, Nobuhisa T, Cui R, et al. Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning. Nature. 2006;443(7109):340-344.
23. Cui R, Widlund HR, Feige E, et al. Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell. 2007;128(5):853-864.
24. Carreira S, Goodall J, Denat L, et al. Mitf regulation of Dia1 controls melanoma proliferation and invasiveness. Genes Dev. 2006;20(24):3426-3439.
25. Kawakami A, Fisher DE. The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology. Lab Invest. 2017;97(6):649-656.
26. Elkoshi N, Parikh S, Malcov-Brog H, et al. Ataxia Telangiectasia Mutated Signaling Delays Skin Pigmentation upon UV Exposure by Mediating MITF Function toward DNA Repair Mode. J Invest Dermatol. 2023;143(12):2494-2506.e4.
27. Hugo W, Zaretsky JM, Sun L, et al. Genomic and Transcriptomic Features of Response to Anti-PD-1 Blockade in Melanoma. Cell. 2016;165(1):35-44.
28. Premi S, Wallisch S, Mano CM, et al. Photochemistry. Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure. Science. 2015;347(6224):842-847.
29. Chemla Y, et al. HLA export by melanoma cells decoys cytotoxic T cells to promote immune evasion. Cell. 2025.
30. González Maglio DH, Paz ML, Leoni J. Sunlight Effects on Immune System: Is There Something Else in addition to UV-Induced Immunosuppression? Biomed Res Int. 2016;2016:1934518.
31. Schade N, Esser C, Krutmann J. Ultraviolet B radiation-induced immunosuppression: Molecular mechanisms and cellular alterations. Photochem Photobiol Sci. 2005;4(9):699-708.
32. Schwarz T. Mechanisms of UV-induced immunosuppression. Keio J Med. 2005;54(4):165-171.
33. Jessup JM, Hanna N, Palaszynski E, Kripke ML. Mechanisms of depressed reactivity to dinitrochlorobenzene and ultraviolet-induced tumors during ultraviolet carcinogenesis in BALB/c mice. Cell Immunol. 1978;38(1):105-115.
34. Denkins Y, Fidler IJ, Kripke ML. Exposure of mice to UV-B radiation suppresses delayed hypersensitivity to Candida albicans. Photochem Photobiol. 1989;49(5):615-619.
35. Howie S, Norval M, Maingay J. Exposure to low-dose ultraviolet radiation suppresses delayed-type hypersensitivity to herpes simplex virus in mice. J Invest Dermatol. 1986;86(2):125-128.
36. Jeevan A, Kripke ML. Effect of a single exposure to ultraviolet radiation on Mycobacterium bovis bacillus Calmette-Guerin infection in mice. J Immunol. 1989;143(9):2837-2843.
37. Romerdahl CA, Donawho C, Fidler IJ, Kripke ML. Effect of ultraviolet-B radiation on the in vivo growth of murine melanoma cells. Cancer Res. 1988;48(14):4007-4010.
38. Maliah A, et al. Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy. Nat Commun. 2024.
39. Maliah A, et al. Systemic effect of ultraviolet radiation on lung cancer growth. Sci Rep. 2026.
40. Kaur A, Webster MR, Marchbank K, et al. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature. 2016;532(7598):250-254.