Sex-Related Differences in Immunotherapy Toxicities: Insights into Dimorphic Responses
Simple Summary
Abstract
1. Introduction
2. Methods
3. Biological Factors Underpinning Gender-Related Differences in Drug Toxicities: The Role of Sex Hormones and Pharmacokinetics
4. Sex Differences in Immunity and Antitumor Response
4.1. Sex Differences and Immunity
4.2. Sex Differences and Antitumor Response
5. Sex-Based Differences in Efficacy and Immune-Related Toxicities of Immune Checkpoint Inhibitors: Evidence and Insights
5.1. Sex Differences and ICIs Efficacy
5.2. Sex Difference and irAE Incidence
Study | Pts | Type of Cancer | ICIs | irAE Type | Incidence (Female vs. Male) | OR (Female vs. Male) 95% CI [p = Value] |
---|---|---|---|---|---|---|
Unger et al. (2022) [59] | 2319 | Multiple cancer types | Anti-PD-1/PD-L1 +/− Anti-CTLA-4 | Hematologic; Cardiotoxicity; Skin; Endocrine; GI; Neurological | 56.6% vs. 48.8% (severe) | 1.49 (1.24–1.78) p < 0.001 |
Duma et al. (2021) [66] | 476 | Melanoma; NSCLC | Anti-PD-1 | Endocrine; Arthralgia; Pneumonitis | 67% vs. 60% vs. 46% | 1.12 (1.08–1.20) p < 0.04 |
Kudura et al. (2022) [69] | 103 | Melanoma | Anti-PD-1; Anti-PD-1 + Anti-CTLA-4 | Skin; Thyroid, | 45% vs. 32% | / |
Bui et al. (2022) [67] | 235 | Melanoma | Anti-PD-1, PD-L1, CTLA4, PD-1 + CTLA-4 | Dermatological | 62.4% vs. 48.6% | 2.1 (1.2–3.8) p = 0.01 |
Valpione et al. (2018) [71] | 140 | Melanoma | Anti-CTLA-4 | Dermatological, GI, Endocrine | / | 1.5 (1.06–2.16) p = 0.22 |
Jing et al. (2021) [65] | 2982 | Melanoma, NSCLC, RCC | Anti-PD-1, PD-L1 | / | NSCLC 38.7% vs. 43.8%; Melanoma 39% vs. 45% | Pooled OR 1.19 (0.91–1.54); [p = 0.21] NSCLC: 0.97 (0.58–1.62); [p = 0.92] Melanoma 1.28 (1.01–1.63) [p = 0.04] |
Miceli et al. (2023) [73] | 204 | Multiple cancer types | Anti-PD-1/PD-L1 +/− Anti-CTLA-4 | Endocrine, hepatic | 27% vs. 11% | / |
Wahli et al. (2022) [74] | 689 | Multiple cancer types | Anti-PD-1, PD-L1, CTLA-4, Anti-PD-1 + Anti-CTLA-4 | 38.4% vs. 28.1% | / | |
Muir et al. (2021) [63] | 1246 | Melanoma | Anti-PD-1, Anti-PD-1 + Anti-CTLA-4 | Thyroid | / | 1.62 (1.27–2.08) p < 0.001 |
6. Mechanisms Underlying Sex Dimorphism in irAEs
7. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
Abbreviations
5-FU | 5-fluorouracil |
CAF | cancer-associated fibroblast |
CTAs | cancer–testis antigens |
CYP2C19 | Cytochrome P450 2C19 |
CYP2D6 | Cytochrome P450 2D6 |
CYP3A4 | Cytochrome P450 3A4 |
DCs | Dendritic cells |
E2 | 17-β-estradiol |
GFR | Glomerular filtration rate |
HLA | Human leukocyte antigen |
HSPA5 | Heat shock protein family A (Hsp70) member 5 |
IgG | Immunoglobulin G |
IgM | Immunoglobulin M |
IL-17 | Interleukin 17 |
LAG3 | Lymphocyte-activation gene 3 |
LAGE-1 | L antigen family member 1 |
MAGE-A1 | Melanoma-associated antigen A1 |
MAGE-A3 | Melanoma-associated antigen A3 |
MAGE-A4 | Melanoma-associated antigen A4 |
MANF | Mesencephalic astrocyte-derived neurotrophic factor |
NY-ESO-1 | New York esophageal squamous cell carcinoma 1 |
RCTs | Randomized controlled trials |
SNPs | Single nucleotide polymorphisms |
TCR | T-cell receptor |
TIGIT | T-cell immunoreceptor with Ig and ITIM domains |
TIM-3 | T-cell immunoglobulin and mucin-domain containing-3 |
TLR | Toll-like receptor |
TME | Tumor microenvironment |
TMZ | Temozolomide |
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Canzian, J.; Conforti, F.; Jacobs, F.; Benvenuti, C.; Gaudio, M.; Gerosa, R.; De Sanctis, R.; Zambelli, A. Sex-Related Differences in Immunotherapy Toxicities: Insights into Dimorphic Responses. Cancers 2025, 17, 1054. https://doi.org/10.3390/cancers17071054
Canzian J, Conforti F, Jacobs F, Benvenuti C, Gaudio M, Gerosa R, De Sanctis R, Zambelli A. Sex-Related Differences in Immunotherapy Toxicities: Insights into Dimorphic Responses. Cancers. 2025; 17(7):1054. https://doi.org/10.3390/cancers17071054
Chicago/Turabian StyleCanzian, Jacopo, Fabio Conforti, Flavia Jacobs, Chiara Benvenuti, Mariangela Gaudio, Riccardo Gerosa, Rita De Sanctis, and Alberto Zambelli. 2025. "Sex-Related Differences in Immunotherapy Toxicities: Insights into Dimorphic Responses" Cancers 17, no. 7: 1054. https://doi.org/10.3390/cancers17071054
APA StyleCanzian, J., Conforti, F., Jacobs, F., Benvenuti, C., Gaudio, M., Gerosa, R., De Sanctis, R., & Zambelli, A. (2025). Sex-Related Differences in Immunotherapy Toxicities: Insights into Dimorphic Responses. Cancers, 17(7), 1054. https://doi.org/10.3390/cancers17071054