Melanoma, a malignant tumor originates from melanocytes, representing a significant malignancy with substantial impact on public health (1, 2). Its remarkable invasiveness and high metastatic potential present a considerable clinical challenge. Melanoma ranks fifth among newly diagnosed cancer cases, accounting for approximately 4-6% (3). While the incidence trends of melanoma have been thoroughly documented, the mortality trends, particularly in relation to the impact of therapeutic innovations, remain less understood. Evaluating the mortality trends is of paramount importance, as the potential introduction of melanoma screening programs and advancements in treatment are anticipated to exert a range of influences on future mortality rates. This analysis is essential for informing public health strategies and optimizing melanoma management protocols. Furthermore, it is imperative to disaggregate the incidence-based mortality and survival rates by gender, given the distinct prevalence patterns of melanoma among different sexes (4–6). This stratification will provide a more nuanced understanding of the disease’s epidemiological profile and inform targeted interventions and research initiatives.

The treatment of melanoma has historically posed significant challenges, with limited efficacy observed in response to conventional chemotherapy regimens. In recent years, significant advancements have trans-formed the melanoma treatment arena, with the emergence of targeted therapies and immunotherapies profoundly altering the prognosis for patients. These innovative approaches have not only expanded the treatment options available but also improved the survival quality and overall survival for individuals afflicted with this aggressive form of skin cancer. The BARF mutation in melanoma serves as a paradigmatic illustration. Therapeutic agents designed to target cancers harboring BRAF mutations represented a pioneering class of targeted therapies for the treatment of advanced melanoma. Vemurafenib and dabrafenib, which selectively target the BRAF-V600E mutation, exert a negligible effect on the wild-type BRAF protein (7–9). The National Comprehensive Cancer Network (NCCN) advocates for BRAF mutation status testing in high-risk melanoma cases to inform clinical management strategies. The U.S. Food and Drug Administration (FDA) first approved an immune checkpoint inhibitor (ICI) therapy for melanoma in 2011, ipilimumab, which is an antibody that targets the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (10). This approval was followed by the FDA’s endorsement of anti-programmed cell death protein 1 (PD-1) antibodies pembrolizumab and nivolumab in 2014, marking further advancements in immunotherapeutic options for melanoma treatment (11, 12). The therapeutic repertoire was further expanded in 2015 with the FDA approval of the combinatorial regimen of ipilimumab and nivolumab, heralding a new era in melanoma treatment strategies (13). However, a comprehensive evaluation of the impact of therapeutic advancements on melanoma’s population-level mortality remains elusive.

Employing the incidence-based mortality approach, this study delineates melanoma’s mortality trends in the United States from 2001 to 2019. The analysis incorporates gender-stratified data to assess the influence of incidence rates and melanoma-specific survival on mortality trends. This approach reveals distinct gender-related patterns and highlights disparities in melanoma incidence and patient outcomes.

In this investigation, we elucidate the mortality trends among melanoma patients, stratified by gender, while incorporating the dynamics of incidence and survival patterns. We have observed an improvement in the mortality since 2010, following the FDA approval of targeted therapies and immunotherapies. This improvement was particularly pronounced between 2015 and 2019, shortly after the recommendation of com-bination immunotherapy, with a significant reduction in incidence-based mortality, especially among male patients. However, no significant change was observed in the mortality rates among female patients. Significantly, within the female patient population, postmenopausal patients seemed to derive greater benefits from immunotherapy compared to their younger counterparts.

Melanoma prevention presents ongoing challenges, with epidemiological surveys revealing a substantial 320% escalation in melanoma incidence from 1975 to 2018 (19). Our research shows that there was no significant downward trend in the incidence of melanoma during the observed time period. Conversely, there was an increase in melanoma incidence from 2010 to 2015, which aligns with previous observations. The screening of individuals with risk factors and high-risk groups should be further strengthened to ensure a comprehensive evaluation.

During the preceding decade, the therapeutic domain for melanoma has undergone profound evolution. Specifically, melanoma incidence-based mortality was escalating prior to 2010. The introduction of targeted therapy and immunotherapy subsequently transformed the treatment landscape for advanced melanoma. Before these treatments, Dacarbazine stood as the sole FDA-approved chemotherapy agent for metastatic melanoma, yielding response rates between 7% and 12%, and a median overall survival (mOS) ranging from 5.6 to 7.8 months (8). A study published in N Engl J Med in 2010 showed that BRAF inhibitors effectively treat most patients with metastatic melanoma carrying the BRAF V600E mutation, leading to complete response or partial response (7). The BRIM-3 clinical trial substantiated that vemurafenib markedly enhanced OS and progression-free survival (PFS) in patients with untreated, metastatic melanoma harboring the BRAF V600E mutation, as compared to the use of dacarbazine (8). Furthermore, vemurafenib was designated the inaugural therapy for advanced melanoma to receive FDA approval in 2011. The advent of targeted therapy initiated a decline in the previously escalating melanoma mortality rates. Concurrently, the clinical deployment of immunotherapy has been transformative for the treatment paradigms of various cancers, notably with melanoma being among the pioneering neoplasms to benefit from such interventions. In 2011, the FDA sanctioned ipilimumab, a fully human monoclonal antibody, for metastatic melanoma therapy (10). Subsequently, a suite of agents directed against the PD-1/PD-L1 pathway, including nivolumab, pembrolizumab, and atezolizumab, have been authorized for melanoma treatment (12, 20, 21). Recognizing the potential for synergistic effects between distinct immunotherapeutic classes to activate diverse components of the immune response, clinical development advanced to encompass trials of combination immunotherapies. Clinical trials have demonstrated that combination immunotherapy significantly benefits melanoma patients, including the CheckMate-069 (22, 23) and CheckMate-067 trials (24–26). In 2015, the FDA approved the combination therapy of ipilimumab and nivolumab, further expanding treatment options and heralding a new era in melanoma treatment strategies (13). Our statistical results corroborate that the improvement in melanoma survival coincides with the introduction and approval of targeted therapies and immunotherapies. Given the nature of the study, we cannot dismiss the possibility that changes in other contributing factors may have influenced the declining melanoma mortality. While treatment methods can have an immediate effect on mortality, upstream factors such as changes in risk factors tend to exert a more gradual and diffuse influence. Therefore, it is less likely that any alterations in risk factors had an immediate impact on the observed rapid decline in mortality. However, caution must be exercised when attributing improved survival solely to immunotherapy therapies without data regarding their utilization among patients.

To our knowledge, this study presents the inaugural evidence of a marked sex-based disparity in the impact of immunotherapy advancements on melanoma, as measured by incidence-based mortality. The results revealed a significant downward trend in male mortality from 2015 to 2019, while female mortality exhibited stability. In terms of survival rates, there was a notable disparity between the two groups in 2000. The 2-year relative survival rate for male increased from 92.5% in 2001 to 95.1% in 2019, whereas the corresponding rate for female patients stood at 95.7% in 2001 and gradually rose to reach 96.7% after two decades. Despite being higher than that of male patients, the survival rates have further converged. And it indicated a greater benefit for male patients from innovative treatment strategies. A study in 2022 found that the baseline characteristics, peripheral inflammatory response, and treatment toxicity differ significantly between male and female patients with advanced melanoma under-going immunotherapy (27). More notably, our findings indicate that immunotherapy appears to be more beneficial for post-menopausal female patients. Moreover, another study’s findings raise a concern: a higher incidence of melanoma is observed in women during their early life stages, whereas men exhibit increased rates in later life (28). The findings suggest that estrogen and progestins might exert a significant influence on melanoma pathogenesis and its resistance to immunotherapy. Research indicates that sex-based immuno-logical variations, which affect both innate and adaptive immune responses, are shaped by sex hormones and the genetic profiles that differ between males and females (29–32).Early studies report female tumor immunogenicity is low, leads to lower the curative effect of immunotherapy (33). Our results hold implications for clinical practice and inform the direction of future research: primarily, the evaluation of immunotherapy strategies must consider gender as a potential risk and benefit factor, although additional studies are warranted to confirm this association and to elucidate the extent of gender’s influence on the efficacy of immunotherapies. Secondly, when designing new immunotherapy studies, it is crucial for researchers to ensure equal participation of both women and men in clinical trials. Lastly, special consideration should be given to women before and after menopause as they may exhibit different reactions to immune therapy.

Although the study provides valuable information, it is crucial to acknowledge its limitations. Firstly, the SEER database lacks comprehensive data on targeted therapy and immunotherapy. Secondly, the relatively short follow-up duration after immunotherapy in melanoma patients within the SEER database hinders obtaining additional long-term survival outcomes. Thirdly, the prognosis provided by the SEER database is limited to survival time and does not include analysis of objective response rate (ORR), disease control rates (DCR), PFS, and quality of life. Finally, it is important to emphasize that initially immunotherapy was approved for the treatment of patients with unresectable or metastatic melanoma. However, subsequent publication of clinical trial results has expanded the application of immunotherapy in the broader spectrum of melanoma treatment. Nevertheless, it should be noted that this study included all patients with melanoma, which may introduce a certain degree of confounding bias. Based on the findings from clinical studies, there is evidence supporting the positive impact of immunotherapy across majority stages of melanoma; however, further validation in real-world settings and longer follow-up periods are warranted.

Our study indicates that since 2015, although the incidence of melanoma has not decreased, the clinical application of targeted therapies and immunotherapies has led to a significant reduction in incidence-based mortality. Combination immunotherapy treatment strategies have yielded greater benefits for male patients, while female patients, particularly those who are young, have not experienced significant advantages. Consequently, the assessment of risks and benefits of immunotherapy strategies in clinical research should take into account the patients’ gender. Further confirmation of this finding is warranted through larger-scale trials.