Skin cancer comprises a spectrum of malignant neoplasms originating in the epidermis, affecting individuals across all racial, socioeconomic strata, and geographic regions (1–3). The global burden of skin cancer has demonstrated a significant increase (1, 2, 4). In England, the incidence rate of skin cancer was four-fold higher relative to other malignancies (5). According to the latest TNM classification system, skin cancer is categorized into several subtypes, including basal-cell carcinoma (BCC), squamous-cell carcinoma (SCC) (collectively designated as non-melanoma skin cancer, or NMSC, ICD-10: C44-C44.9), melanoma (ICD-10: C43-C43.9), and other rare subtypes (6). BCC constitutes the most prevalent form of skin cancer, accounting for 80% of NMSC cases (7), with an annual incidence growth rate of 3–10% (8). Recent epidemiological estimates indicate that the annual incidence of BCC in the United States approaches 2,000,000 cases (9), while in the United Kingdom, the incidence was documented at 3 cases per 1,000 individuals in 2015, with a projected annual increase of approximately 5% (5). SCC represents the second most prevalent variant of NMSC, with an incidence rate of approximately 1,035 cases in males and 472 cases in females per 100,000 person-years (10). Melanoma represents a highly aggressive form of cutaneous malignancy, characterized by a steadily increasing global incidence rate (11). From 1990 to 2017, the incidence of SCC increased by 310%, melanoma by 161%, and BCC by 77% (4), resulting in significant healthcare costs worldwide, with medical expenses expected to rise substantially in subsequent decades (12–15). Skin cancer represents a substantial global health concern with considerable socioeconomic implications (16, 17). To address the substantial healthcare burden associated with total skin cancer and its subtypes, comprehensive longitudinal analyses of their epidemiological patterns are imperative. Despite the fact that extant literature has documented a persistent increase in the disease burden associated with various skin cancer subtypes (2, 3), these investigations predominantly focus on individual skin cancer subtypes rather than adopting a collective analytical approach (2, 3, 7). Considerable deficiencies remain regarding the long-term epidemiological trends of skin cancer and its comprehensive impact on population health.

Although skin cancer encompasses several types (such as Merkel cell carcinoma, sebaceous carcinoma, and eccrine/apocrine carcinoma), the GBD 2021 database estimates the burden of only three major types: SCC, BCC and melanoma, which together account for more than 90% of all skin cancer cases (18). Therefore, this research focuses on these three types as the primary subjects for analyzing the global burden of skin cancer. Through conducting a comprehensive epidemiological analysis, we aim to inform evidence-based prevention and treatment strategies, ultimately contributing to optimized global health outcomes.

Skin cancer represents a substantial public health concern, imposing a significant burden on healthcare systems worldwide (25). Although multiple studies have documented the burden of melanoma, SCC, and BCC, these investigations predominantly have utilized GBD 2017 and GBD 2019 datasets (3, 4) and have lacked comprehensive global health inequality analyses or future projections. The present study provides a novel and comprehensive assessment of the global burden of total skin cancer, while simultaneously conducting a detailed comparative analysis of the three major subtypes. The main findings are as follows: First, skin cancer ASIR increased from 1990 to 2021, while ASDR significantly decreased. Second, geographical heterogeneity existed in distribution of histological subtypes. Third, skin cancer burden demonstrated age-dependent progression with compositional variance in subtypes across age groups. Fourth, sex disparities intensified beyond age 55, with increasing longitudinal divergence. Fifth, both the ASIR and ASDR of total skin cancer showed non‑linear associations with SDI. Sixth, international disparities in skin cancer burden demonstrated a decreasing trend. Finally, projections to 2040 indicate a continued increase in total skin cancer ASIR, accompanied by a persistent decline in total skin cancer ASDR.

From 1990 to 2021, the ASIR of total skin cancer demonstrated an upward trend, with comparable patterns observed across three major subtypes. This finding corroborates previous research (2–4, 16, 26) that documented an elevated incidence of melanoma, BCC and SCC. Ultraviolet radiation (UVR) is the major etiologic agent in the development of skin cancers. UVR contributes to skin cancer through a dual mechanism involving direct DNA damage and indirect immunosuppressive and oxidative damage. UVB radiation (280–320 nm) is directly absorbed by thymine bases in DNA, resulting in the formation of cyclobutane pyrimidine dimers (CPDs) and 6–4 photoproducts (27). UVA radiation (320–400 nm) primarily induces DNA damage through the excitation of endogenous chromophores, which subsequently generate reactive oxygen species (28). When UV-induced DNA damage is not efficiently repaired, mutations accumulate in key driver genes such as TP53 and BRAF, thereby promoting skin carcinogenesis (28). Furthermore, ultraviolet radiation has been shown to induce immunosuppression through the activation of Langerhans cell migration and the subsequent induction of IL-4 secretion by NKT cells (29). Advancing age is associated with compromised DNA repair capacity, including the decline of nucleotide excision repair (NER) and base excision repair (BER) mechanisms (30); diminished immune surveillance, characterized by reduced Langerhans cell populations (31) and impaired T-cell function; and the establishment of a pro-carcinogenic microenvironment resulting from the accumulation of senescent cells, such as fibroblasts (32), which secrete senescence-associated secretory phenotype (SASP) factors. These interconnected processes synergistically promote mutation accumulation in skin cells, ultimately facilitating malignant transformation and the development of skin cancer. Beyond the established impact of ultraviolet radiation exposure (33–35) and demographic aging (36), the extensive implementation of therapeutic modalities has been associated with the increased skin cancer prevalence. The use of immunosuppressive agents, including azathioprine (37) and calcineurin inhibitors (38), is associated with DNA damage while simultaneously inhibiting DNA repair mechanisms. Consequently, organ transplant recipients exhibit substantially elevated risks of BCC and SCC, with incidence rates exceeding those in the general population by orders of magnitude (39, 40). Furthermore, radiation therapy is characterized by the generation of free radicals and reactive oxygen intermediates, thereby damaging rapidly dividing cells in the epidermal basal layer and dermis (41). This process leads to reversible or irreversible DNA damage (41) and has been associated with a 6.3-fold increase in BCC and SCC risk among pediatric cancer survivors who have undergone radiation therapy (42, 43). Additionally, thiazide diuretics are characterized by photosensitizing properties that induce abnormal cutaneous reactions to ultraviolet radiation, thereby establishing a distinct dose–response relationship with BCC and SCC development (44). Previous studies have demonstrated that the risk of BCC and SCC exhibits a dose-dependent relationship with phototherapy sessions utilizing UVA, UVB, and occasionally visible light (45–47). These factors cumulatively account for the more substantial ASIR elevation observed in SCC and BCC relative to melanoma. Consequently, enhanced surveillance and systematic management of SCC and BCC burden are imperative in populations with exposure to these therapeutic interventions. Moreover, individuals with HIV who delay the initiation of antiretroviral therapy experience permanent loss of cutaneous memory T cells (48), thereby increasing their susceptibility to skin cancer development. An 80% elevated risk has been observed in comparison to HIV-negative individuals, with SCC being predominantly affected (49). Therefore, the global elevation in HIV prevalence (50) contributes to the increasing ASIR of skin cancers. Additionally, both human papillomavirus (HPV) (51) and diabetes (52) have been identified as contributory factors in skin cancer pathogenesis. The early proteins E6 and E7 of β-HPV have been shown to be capable of altering cellular responses to UV-induced stress and promoting the survival of DNA-damaged cells (51). In diabetic patients, elevated insulin and insulin-like growth factor (IGF) levels are associated with enhanced cellular proliferation and the upregulation of oncogenic epidermal growth factor receptors, subsequently inhibiting apoptosis and facilitating malignant transformation (53). Consequently, the increasing prevalence of both HPV (54) infection and diabetes mellitus (55) contributes to the rising incidence of skin cancer. Although previous investigations (56–58) have comprehensively summarized specific risk factors for skin cancers, the observed heterogeneity among these studies emphasizes the necessity for further research to elucidate risk factor profiles and develop targeted early prevention strategies. Furthermore, multiple factors have contributed to the improved detection rates of skin cancer: the global implementation of skin cancer screening programs (59–61), the promotion of self-skin examination (SSE) and total body skin examination (TBSE) protocols (62), and technological advancements including biosensors (63), computer-aided diagnosis systems (64), and teledermatoscopy platforms (65)—all enhancing diagnostic accuracy for skin malignancies. Notably, our temporal analysis of total skin cancer ASIR revealed a distinctive epidemiological pattern: a steady increase from 1990 to 2005, followed by a consistent decline from 2006 to 2019, and a significant resurgence from 2020 to 2021. Specifically, the ASIRs of BCC and SCC exhibited increasing trends from 2019 to 2021, whereas that of melanoma showed a declining trend, consistent with previous findings (66). The plateau in global skin cancer ASIR observed after the early 2000s can be attributed to the widespread implementation of public education and early detection programs, as supported by previous studies (67, 68). The mechanisms underlying the changes in skin cancer subtype ASIR between 2019 and 2021 encompass several key factors. Primarily, the COVID-19 pandemic has substantially influenced the differences in ASIRs for skin cancer subtypes between 2019 and 2021. Previous studies have demonstrated that severe and hospitalized COVID-19 cases are negatively correlated with melanoma risk (OR < 1) (69). Furthermore, the disruption of routine medical services and decreased screening compliance associated with COVID-19 have been detrimental to skin cancer diagnosis and detection. When combined with the suboptimal sensitivity of melanoma self-examination methods (70), melanoma diagnosis and detection have become increasingly challenging during the COVID-19 pandemic. In contrast, the distinctive clinical presentations of SCC and BCC (71, 72) have facilitated enhanced detection sensitivity, thereby mitigating the impact of healthcare access restrictions in 2020. Consequently, the ASIR of BCC and SCC has increased between 1990 and 2021, while melanoma ASIR has decreased.

From 1990 to 2021, the ASDR of total skin cancer demonstrated a declining trend, predominantly attributable to melanoma. This observation aligns with the findings of Sun et al., who documented a 16.8% reduction in melanoma ASDR during the corresponding period (2). The implementation of skin self-examination programs and public health education initiatives over recent decades (73–75) has facilitated early detection and intervention for skin cancers, resulting in a reduction in the overall disease burden. In contrast, BCC exhibited a significant increase in ASDR (EAPC = 1.64). This upward trend resulted from several contributing factors. The high recurrence rate (76), coupled with prolonged treatment and rehabilitation protocols associated with BCC, contributes to its elevated ASDR. Additionally, the escalating ASIR of BCC, in conjunction with demographic aging and the accumulation of untreated or delayed-treatment cases, has contributed substantially to the increasing disease burden. The extensive treatment duration and comprehensive rehabilitation regimen required for BCC emphasize the imperative for enhanced continuity of care. Consequently, healthcare systems should establish robust follow-up protocols to facilitate optimal post-treatment recovery and enable systematic surveillance. Such measures would expedite the identification of potential recurrences and mitigate the cumulative disease burden through prompt clinical intervention.

Given that DALYs can be decomposed into years lived with disability (YLD) and years of life lost (YLL), exploring the potential impact of both components on the observed findings is essential, although specific analysis of YLD and YLL changes in skin cancer was not conducted in this study. Since YLDs represent the health loss experienced by patients living with disease, and YLLs represent the years of life lost due to premature mortality caused by the disease, the increasing ASIRs of total skin cancer are associated with an elevated burden of YLDs. For skin cancer, the majority of cases are non-fatal (77, 78) when compared to other malignancies. Consequently, YLDs represent the principal component of DALYs, whereas YLLs contribute to a relatively smaller proportion. Both BCC and melanoma conform to this pattern. However, for SCC, both ASIRs and ASDRs demonstrated upward trends. Given that SCC exhibits greater local invasiveness and metastatic potential than BCC (79), this condition results in increased mortality, leading to elevated YLLs, while simultaneously indicating that substantial numbers of patients live with the disease long-term, thereby contributing to a greater YLD burden.

The epidemiological burden of skin cancer demonstrates marked geographical heterogeneity. Differential UVR exposure resulting from variations in stratospheric ozone depletion (80), urbanization processes (81), altitude (82), and latitude (83) contributes to this phenomenon. Consistent with previous epidemiological investigations (84), our analysis identified Australasia as the geographical region exhibiting the most substantial skin cancer burden, as evidenced by markedly elevated ASIR and ASDR. This phenomenon is predominantly attributable to the exceptionally high ambient UVR exposure levels prevalent on the Australian continent. Epidemiological investigation has estimated that approximately 63% of melanoma cases and virtually all keratinocyte carcinomas are attributable to cumulative solar radiation exposure (85). Notably, the demographic composition of this region is characterized by predominantly British (33.0%), Australian (29.9%), and Irish (9.5%) ancestries (86). These populations possess limited constitutive melanin levels and lack the physiological factors necessary for effective photoprotection against ultraviolet radiation (87), thereby exacerbating the skin cancer burden in this region. While regular sunscreen application has been demonstrated to prevent approximately 9.3% of NMSCs and 14% of melanoma cases (85), merely 15% of the population adheres to recommended sunscreen application protocols (88). Therefore, targeted regional public health initiatives should prioritize comprehensive sun protection education and awareness programs to enhance adherence to recommended photoprotective behaviors and optimize sunscreen utilization rates.

The burden of total skin cancer demonstrates a positive correlation with age, exhibiting a marked elevation after the age of 50, as evidenced by ASIRs and ASDRs. Analogous patterns were observed in melanoma, BCC, and SCC, which corroborates previous findings (1, 2, 89). Age constitutes a significant determinant in the pathogenesis of cutaneous malignancies. Previous investigations (90) have elucidated the underlying mechanisms, delineating age-related and ultraviolet (UV)-induced mutations as two distinct mutational pathways. These dual pathways mediate carcinogenesis not only in melanoma but also in BCC and SCC. Notably, UVB-induced mutations in keratinocytes during childhood and adolescence can accumulate temporally, contributing to carcinogenesis (91). This phenomenon is particularly significant considering that cumulative solar radiation exposure during these formative years accounts for the predominant proportion of an individual’s overall UV exposure throughout the lifespan (92). Although skin cancers are relatively infrequent in pediatric and adolescent populations, photoprotection remains imperative. Additionally, the ASIR of melanoma in males over 90 demonstrated a significant decline, consistent with previous epidemiological findings (4). Multiple age-associated biological processes contribute to this phenomenon, including stem cell senescence (93) and alterations in the microenvironmental milieu (94). Specifically, stem cell senescence is observed to promote tumor initiation through the Nupr1–lipocalin-2 pathway via the induction of functional iron deficiency (93). Age-induced senomorphics have been shown to suppress pro-tumorigenic signaling through the inhibition of SASP factor secretion, thereby alleviating chronic inflammation (95). Moreover, aging-associated stimuli, including DNA damage, telomere shortening, and oncogene activation, induce cellular senescence, resulting in stable growth arrest of these damaged cells (96, 97). Besides, the proportional distribution of skin cancer burden demonstrated age-dependent variations. With advancing age, the proportional contribution of melanoma to the total skin cancer burden diminished, whereas the proportion attributable to SCC increased. This phenomenon is attributed to differences in the etiological patterns of UVR exposure among skin cancer subtypes. Melanoma is primarily associated with intermittent and high-intensity solar radiation exposure (98, 99), which tends to decrease in geriatric populations due to health-related mobility and functional limitations (100). Furthermore, this phenomenon has been associated with a “plateau effect” in screening and self-examination frequencies. Although routine skin examinations remain capable of detecting early-stage melanoma, the marginal benefits of such screening are diminished in older adult populations (101). Consequently, the proportional contribution of melanoma to the overall disease burden exhibits a progressive decline with advancing age. Conversely, SCC is associated with cumulative and chronic low-dose ultraviolet radiation exposure (98, 99), which accumulates with advancing age, thereby resulting in an increased burden of SCC among older adult populations. These findings underscore the significance of ultraviolet radiation protection across all demographic age cohorts, while simultaneously emphasizing the necessity for age-stratified prevention strategies calibrated to address distinct patterns of ultraviolet exposure and cutaneous malignancy risk profiles.

Sex-specific analysis revealed significantly elevated ASIR and ASDR in males compared to females for total skin cancer, with this disparity progressively amplifying with advancing age. This pattern was consistent across all three histological subtypes of skin cancer, highlighting sex-based biological differences as critical determinants in skin cancer epidemiology. This observed disparity results from a multitude of factors. Behavioral differences are considered the primary drivers of sex- disparities in skin cancer (102); women demonstrate greater photoprotection awareness and protective behaviors than men (103, 104), and exhibit higher likelihood of performing skin self-examinations (105). Furthermore, skin biology is profoundly influenced by sex hormones, including estrogens, androgens, and progesterone (106–108). Among these hormones, androgens have been demonstrated to exert immunosuppressive effects, whereas estrogens are generally considered immunoenhancing agents (109). Thus, sex-specific differences in behavior and hormonal milieu are hypothesized to underlie sex-related disparities in skin cancer incidence.

The skin cancer burden demonstrates a significant association with SDI. A turning point was observed at an SDI of approximately 0.7 to 0.8, which represents the interactive effect between “health transition” and “public health saturation.” During the low to moderate SDI stage (0–0.8), both ASIR and ASDR demonstrated a general upward trend. This finding is consistent with previous epidemiological studies (110, 111), which have reported a positive correlation between cancer incidence and socioeconomic development. Multiple factors contribute to this epidemiological pattern, including demographic aging, elevated air pollution levels (112), increased light pollution (113), and enhanced accessibility to skin cancer screening protocols that facilitate early detection. Furthermore, economic development and improved living standards result in lifestyle changes, which lead to increased ultraviolet exposure through outdoor recreation, sunbathing, and artificial tanning, thereby contributing to the rise in skin cancer incidence. Additionally, the increase in ASIR at this stage potentially contributes to the observed trend in ASDR through its proportional impact on YLD calculations within the DALY framework. At this stage, health systems and public awareness of skin cancer have not been adequately developed, while sun protection awareness and early screening systems remain imperfect, resulting in continued growth of ASIRs and ASDRs. During the moderate-to-high and high SDI stages (≥0.8), ASDR began to decline, while ASIR continued to increase. At this stage, public health interventions achieve “critical density,” which is characterized by elevated health literacy and heightened disease awareness (114). In conjunction with advanced diagnostic modalities and therapeutic interventions (115, 116), these factors have precipitated the observed decline in ASDR. At this stage, prevention benefits begin to exceed risk growth rates, thereby establishing an inflection point. In conclusion, the inflection point—at an SDI of approximately 0.7 to 0.8— represents an equilibrium between lifestyle risks associated with economic and social development and the implementation of mature public health prevention and control systems. Prior to this inflection point, risk accumulation predominates; subsequently, large-scale prevention effects become evident. Therefore, low- and middle-SDI regions need to implement effective measures to address their continuously rising incidence and DALYs. However, the increasing cancer burden in these regions presents unique challenges to their already fragile healthcare and economic infrastructure. While previous research has demonstrated that early detection represents an effective strategy for controlling skin cancer (117), prioritizing early detection cannot be considered effective in low- and middle-income countries, where limited downstream resources will be overwhelmed by the inevitable increase in diagnostic volume (118). Therefore, optimal utilization of currently limited resources must be achieved. To achieve this objective, based on recommendations proposed by Timothy et al. (119), the following enhancements are required in low- and middle-SDI regions: (A) enhancement of skin cancer health services research and policy planning capacity; (B) establishment of high-quality health data sources; (C) strengthening of skin cancer-related economic evaluations; (D) exploration and localization of high-quality skin cancer control models; and (E) optimization of early detection strategies to prevent downstream resource overload.

Skin cancer burden exhibits significant health disparities, predominantly attributable to variations in socioeconomic status (SES). Substantial epidemiological evidence demonstrates that SES influences oncological outcomes through multiple mechanistic pathways (120–122), including health literacy (123), healthcare accessibility (124), and psychosocial resource allocation (125), which collectively modulate disease incidence, prognostic indicators, screening adherence, and therapeutic accessibility (126). Our analysis reveals narrowing disparities across socioeconomic strata, evidenced by decreasing SII metrics. Implemented public health policies, targeted interventions, and equitable social health services effectively ameliorated health outcomes among lower-SES populations, thereby diminishing the healthcare disparities between disadvantaged and advantaged socioeconomic cohorts. However, the skin cancer burden remains concentrated among disadvantaged populations. While high-SES cohorts exhibit higher melanoma and BCC incidence rates (127–129), lower-SES populations experience inferior clinical outcomes attributable to the limitations in health literacy, healthcare access, and prevention implementation. Consequently, healthcare policies should be strategically calibrated to address distinctive characteristics of diverse socioeconomic strata, prioritizing healthcare accessibility and quality to reduce disparities in skin cancer outcomes.

Based on predictive modeling, total skin cancer ASIR is projected to increase while ASDR is expected to continue declining through 2040, confirming previous findings (3, 4). This phenomenon results from a confluence of factors, including the escalation of high-risk behaviors concurrent with societal development, alongside advances in prevention, diagnosis, and treatment methodologies. Despite appreciable progress achieved through current healthcare management protocols and the projected continued decline in skin cancer ASDR, sustained vigilance toward the skin cancer burden remains imperative, particularly in the context of progressive population aging. While the ASDRs for melanoma and SCC were expected to decrease, BCC ASDR demonstrates an upward trend, indicating policymakers should allocate more resources toward BCC management.

Utilizing the latest GBD 2021 database, this investigation quantifies the burden of total skin cancer, comparatively analyzes its subtype-specific burden distribution, and generates empirical evidence crucial for evidence-based policy formulation. However, several methodological limitations exist. First, the quality and availability of data vary significantly across countries and regions, particularly in resource-limited settings, finally leading to underreporting or estimation bias. Second, this analysis relies on statistical models with inherent assumptions, which introduce uncertainty, particularly when data are sparse or heterogeneous. Third, regional variations in disease definitions, diagnostic criteria, and reporting practices may compromise the comparability of estimates among countries. Fourth, due to data limitations, our analysis was restricted to three major skin cancer subtypes, with other subtypes being excluded from the study.

In conclusion, skin cancer constitutes a substantial and emergent global public health challenge. From 1990 to 2021, the skin cancer ASIR increased while ASDR decreased. Substantial epidemiological disparities exist across countries, regions, age groups, and sex. Implementation of targeted healthcare interventions stratified by regional epidemiology, sex-specific risk profiles, and age-dependent vulnerability factors are imperative for optimizing therapeutic outcomes and mitigating the overall disease burden.