Recent effect of climate change on melanoma burden and emerging therapeutic strategies

Enhanced ultraviolet exposure

The climate change contributed rise in melanoma is primarily due to the increase in ultraviolet radiation (UVR) in specific countries and regions, as a result of continuous ozone layer degradation. Despite global efforts by the Montreal Protocol, the layer of ozone in the stratosphere remains 3-5% lower in mid-latitudes, with a new Arctic ozone hole causing up to 60% more UVR in that region. Surveys on this very topic have reported the drop of ozone layer by 1% associates with an increase of 1-2% melanoma cases.^9,10 Here, UV-B radiation initiates melanoma by directly damaging DNA, forming lesions like cyclobutene pyrimidine dimers (CPD) and 6-4-pyrimidone photoproducts (6-4PP), while UV-A generates ROS (Reactive Oxygen Species) that induce a high level of DNA damage and disrupt cellular functions through interacting with cellular biochemical reactions.¹¹ By some reports, individuals with impaired MC1R signaling, such as those with red hair, are particularly at high risk due to elevated ROS levels. UVR also suppresses local immune responses, allowing the malignant tumor cells to evade detection and spread throughout the body through melanoma progression [Figure 2].¹²

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Figure 2:

Mechanistic illustration of ozone layer depletion and its impact on UV-B radiation exposure and immune suppression. This figure demonstrates the process by which ozone layer depletion increases UV-B radiation penetration to the Earth’s surface. The upper panel shows how a healthy ozone layer filters UV-B radiation, whereas a depleted ozone layer allows more UV-B rays to reach the lower atmosphere. The lower panel depicts the biological consequences of enhanced UV-B exposure, including DNA damage, immune suppression, and cellular oxidative stress. These effects contribute to mutagenesis and increased risk of skin cancer. UVA radiation, while less filtered by ozone, also plays a role in DNA damage and oxidative stress. Collectively, these mechanisms illustrate how ozone depletion amplifies cutaneous and systemic health risks associated with ultraviolet (UV) radiation.

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Rising temperature and behavioral adaptation

Global warming, a major concern for the health Earth, can also be regarded as a major concern for skin cancer due to both its direct biological effects and indirect behavioral modifications. Heat, directly promoting carcinogenesis within the skin, acts as the main contributor to melanoma in the case of global warming. Scientific modeling suggests that a global rise of 2°C in ambient temperature could lead to an 11% increase in skin cancer cases.¹³ Studies at the cellular level provide mechanistic support for this projection, demonstrating that thermal stress, particularly in cells exposed to UV-B radiation, inhibits the programmed apoptosis of UV-damaged cells. While in a normal scenario, cells with significant DNA damage are eliminated through apoptosis to prevent malignant transformation, the heat stress impairs these crucial repair mechanisms and elimination mechanisms, thus prompting the UV-damaged cells to survive longer than usual, which therefore accumulates a greater “mutational burden” and increases their propensity to develop into melanoma. This reveals a complex, multilevel interaction where climate change-induced heat directly disrupts the natural defense of the body against UV-induced skin cancer, suggesting that the impact of the rising temperatures is not only about increased exposures but also about impaired cellular resilience and DNA repair.^11,14

Beyond these cellular effects, global-warming-driven temperature changes also significantly affect and influence human behavior, thus causing abnormal behavioral changes. These frequent climatic changes have altered regional disease patterns, leading to a substantial rise in melanoma incidence. For instance, prolonged warmer conditions encourage individuals to spend more time outside and wear less protective clothing, which increases their UV-exposure. This sudden behavioral shift in some regions translates into prolonged UV-exposures, mainly for outdoor workers, thus heightening the risk of melanoma among them. Furthermore, climate change can instigate human migration patterns, prompting populations to relocate to subtropical regions where UV intensity is naturally higher. This demographic shift exposes individuals to pronounced UV risks they may not have previously encountered, contributing to a global redistribution of melanoma burden.^15,16

Air pollution and cutaneous carcinogenesis

Air pollution, a pervasive consequence of fossil fuel combustion and natural phenomena like wildfires, represents another significant environmental factor contributing to cutaneous carcinogenesis. These mentioned pollutants, including particulate matter and polyaromatic hydrocarbons, directly or indirectly interact with the skin through various mechanism, which therefore activates complex molecular pathways, notably the aryl hydrocarbon receptor, thus triggering inflammation and promoting carcinogenesis within the skin.^17,18

Air pollution and UV exposure can also interact synergistically and induce skin cancers. In this scenario, the pollutants weaken the natural barrier of the skin and break down collagen, which exacerbates the sensitivity of the skin to UV rays. When the proactive mechanism of the skin is compromised, the likelihood of mutations in the skin cells increases significantly, contributing to the development of skin cancers, including basal cell carcinoma, squamous cell carcinoma, and melanoma. This specialized mechanism acts as a double-edged sword to the skin, where the skin gets damaged from both internal cellular pathways and external barrier compromise. This mechanism is mostly shown in areas experiencing high levels of UV radiation and air pollution, which includes urban centers with intense sunlight, where the risk of skin cancer is amplified beyond the sum of individual risks. This necessitates integrated public health strategies that simultaneously address environmental pollutants and promote robust sun protection.^17-19

Evolution of systemic therapies

The development of systematic therapies has been particularly impactful for treating skin cancer. Targeted therapies²² are the therapies that specifically interfere with the molecular pathways involved in cancer growth and progression, and these therapies have demonstrated considerable potential in treating skin cancers.^23,24 For patients with BRAF-mutant melanoma, the introduction of BRAF inhibitors, including vemurafenib, dabrafenib, and encorafenib, and MEK inhibitors, like trametinib, cobimetinib, and binimetinib, has revolutionized the treatment, often used in combination to enhance efficacy and mitigate resistance.^23-25 These agents have significantly improved response rates and survival for a substantial subset of melanoma patients.^22-25

Similar to targeted therapies, immunotherapies^26-28 have also become a cornerstone of modern melanoma management. Immune checkpoint inhibitors (ICIs)^29-31 like nivolumab, ipilimumab, and pembrolizumab, mostly work by unleashing the own immune system of the body to recognize and attack cancer cells, have fundamentally altered the prognosis for many patients with advanced melanoma. Rather than ICIs, there exist other forms of immunotherapy, including oncolytic viruses³² like Talimogene Laherparepvec (T-VEC)³³ and adoptive cell therapies^34,35 such as Lifileucel, which represent further significant strides in harnessing the immune system to fight melanoma [Figure 3].

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Figure 3:

Mechanisms of targeted therapies and immunotherapies in melanoma treatment. This figure illustrates key strategies in melanoma management, including targeted therapies and immunotherapies. On the left, targeted therapies focus on the RAS-RAF-MEK-ERK pathway, with BRAF and MEK inhibitors reducing tumor proliferation and promoting apoptosis. On the right, immunotherapies include ICIs) such as anti-PD-1, anti-P-L1, and anti-CTLA-4 antibodies, which restore T-cell activity against tumors. Additional immunotherapeutic approaches shown include oncolytic viruses that expose tumor antigens to the immune system and adoptive cell therapies like CAR T-cells, genetically engineered to target cancer cells. These modalities collectively enhance anti-tumor immune responses and inhibit melanoma progression.

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Novel and emerging therapeutic approaches

Despite the remarkable successes of the targeted therapies and immunotherapies, there remain significant challenges in treating melanoma, mostly managing its aggressive subtypes, which exhibit inherent or acquired resistance. Thus, this development scenario drives towards novel and emerging therapeutic approaches to combat these aggressive subtypes of melanoma.^36-38

One of these challenges arises in the form of NRAS-mutant melanoma, an aggressive subtype that accounts for approximately 25% of all melanoma cases, which demonstrates frequent resistance to current standard therapies, including both immunotherapy and targeted drugs. New research on this scenario has emerged with a drug called nitrosylation, known as a blocking chemical. This approaches turns NRAS-mutant melanoma cells more sensitive to MEK inhibitors, a class of drugs that target the MEK-ERK pathway crucial for tumor growth. Preclinical studies, done in both laboratory settings and animal models, have reported that the combination of nitrosylation inhibitors and MEK inhibitors leads to significantly slower tumor growth. If deeper details are shown about the compelling mechanism, it will be seen that blocking nitrosylation not only directly sensitizes cancer cells to existing treatments but also triggers immunogenic cell death. This process causes tumor cells to release specific distress signals, following which crucial immune cells, including CD-8 positive T-cells and dendritic cells, are attracted, which proves to be vital for mounting an effective anticancer response, thus enhancing the intrinsic ability of the body to attack the tumor. This dual action of direct tumor inhibition and immune system potentiation offers a new and potentially highly effective pathway for patients who currently have limited treatment options. Therefore, this new research, which overcomes the resistance from an aggressive melanoma subtype, exemplifies the ongoing research paradigm of understanding specific resistance mechanisms to develop more effective, personalized combination therapies for various cancer types.^39,40

Beyond molecular targeting, nanotechnological approaches are becoming highly demanding for the treatment of melanoma and other skin cancer types.^41-43 The process includes the designing of advanced nano-drug delivery systems which can precisely target melanoma cells,⁴³ multifunctional nanomedicines capable of both imaging and therapy,⁴⁴ and lipid-based nano-vesicular systems for improved drug encapsulation and delivery.^45,46 Novel research on polymeric nanoparticles⁴⁷ and magnetic nanoparticle hyperthermia⁴⁸ are also promising new heights to this field in delivering therapeutic agents more efficiently or to induce localized tumor destruction as per their performance in investigation and clinical trials. These new therapeutic strategies aim to pioneer a roadmap to overcome the limitations of conventional therapies, including drug resistance and systemic side effects, by enabling more targeted and localized treatment and delivery, therefore leading to more durable responses for patients [Figure 4].^41-43

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Figure 4:

Emerging therapeutic strategies and nanotechnological innovations for melanoma treatment. The top panel shows new therapies targeting NRAS-mutant melanoma, including nitrosylation inhibitors and dalotuzumab to promote immune activation and tumor suppression. The bottom panel illustrates nanotechnological approaches like nano-drug delivery and polymeric nanosystems for targeted therapy, controlled release, and diagnostic applications.

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Public health and prevention strategies

Despite the advancements of therapeutics against melanoma, the most effective strategy to combat it remains primary prevention. As for the most common primary prevention, it is stated to avoid excessive UV exposure to reduce the time of ultraviolet radiation induction to the skin. This involves consistent daily application of broad-spectrum sunscreen with an SPF of 30-50, even on cloudy days.^49,50 Furthermore, protective clothing, like long-sleeved shirts, long pants, wide-brimmed hats, and UV-blocking sunglasses, provides a significant reduction of UV-radiation exposure to the skin. Seeking shade during the hour of high exposure, particularly from 10 AM to 4 PM, is also recommended for minimizing exposure.^49-51 Contrary to the popular misconception that tanning beds provide a protective ‘base tan,’ artificial tanning devices emit concentrated UVA and UVB radiation that significantly increase the risk of melanoma. Studies have shown that individuals who begin indoor tanning before age 35 have up to a 75% higher risk of developing melanoma. The ultraviolet radiation from these beds damages DNA in skin cells, accelerates photoaging, and suppresses immune responses, all of which contribute to carcinogenesis. Therefore, tanning beds are not a preventive measure but a well-established risk factor for melanoma.⁵² Public health campaigns based on melanoma and skin cancer awareness camps are highly required in order to build behavioral modifications and take preventive measures starting from childhood.^50,51

Beyond the primary prevention, early detection of melanoma plays a crucial role in treating it, as it is easy to minimize the growth of melanoma, let alone eliminate it, if treated in early stages. Here, regular dermatological check-ups may play a crucial role in detecting abnormal moles or suspicious skin lesions, especially for people who are at high risk of melanoma or carry any family medical history of skin cancer.⁵³ Public education on “ABCDEs” of melanoma (Asymmetry, Border irregularity, Color variation, Diameter > 6mm, and Evolving changes) empowers individuals to perform effective self-assessment about their tendency to melanoma and seek professional dermatological help in identifying their melanoma malignancies early on to receive better treatment.⁵⁴ Targeted interventions are also crucial for vulnerable populations, including outdoor workers, fair-skinned individuals, immunosuppressed patients, and those residing in lower socioeconomic contexts, as these groups require heightened public health awareness and tailored preventive strategies.⁵⁵

Healthcare system adaptation and mitigation

The healthcare sector, while on the front line of addressing climate-related health impacts, also significantly contributes to climate change through its own carbon footprint, where it was estimated that cancer care accounts for approximately 4.4% of global emissions. This creates a feedback loop where increased disease burden, partly driven by climate change, leads to more healthcare activity, which in turn increases emissions, further exacerbating climate change and its health consequences. This inherent interconnectedness underscores an ethical and practical imperative for the healthcare sector to not only adapt to climate change but also actively mitigate its own environmental impact.⁵⁶

To achieve sustainability in healthcare sectors, hospitals will require a shifting towards more renewable energy uses, increasing the energy efficiency within the infrastructure, and adopting sustainable procurement practices for medical supplies and equipment. Furthermore, sustainable innovations in service delivery can significantly reduce emissions associated with patient and staff travel, which constitutes a large portion of the carbon footprint of cancer care. Strategies such as increasing the number of satellite centers for localized care, utilizing hypo-fractionated radiotherapy treatments, which require fewer patient visits, and expanding the use of telemedicine can substantially lower emissions. Telemedicine can especially offer the dual benefit of reducing travel-related emissions and improving access to care for patients in remote or underserved populations. Moreover, promoting feasible community-based cancer care generally has a lower carbon footprint compared to centralized hospital-based care.^56,57

Healthcare systems must also focus on the process of continuing health services during hazardous climate events, including floods, wildfires, and hurricanes, which significantly disrupt cancer care, leading to delayed diagnosis, interrupted treatments, and ultimately impacting patient survival. National adaptation policies can play a critical role here, guiding governments and healthcare providers to develop robust strategies for building climate resilience within the health infrastructure.^58,59

Future directions and interdisciplinary collaboration

Despite the significant progress in diagnostics and therapeutics, some research gaps persist in fully understanding the intricate relationship between climate change and skin cancer. As of literature, there is also a pressing need for further primary epidemiological research and systematic reviews, mostly focusing on the impacts in rural settings and considering the influence of social determinants of health on melanoma rates.⁶⁰

Technological integrations may offer promising avenues for future interventions, where AI can play a vital role in analyzing vast environment data to determine individual patient risk profiles, enabling more personalized preventive strategies.⁶¹ Future innovations aiming for advancing wearable UV sensors⁶² and SPF-infused clothing⁶³ can further enhance individual prevention efforts by offering real-time feedback on UV exposure alongside superior physical protection.

Also, policy and advocacy are indispensable components of a comprehensive response, where dermatologists and other healthcare professionals have a crucial role to play in climate advocacy, leveraging their expertise to generate evidence, educate the public, and champion global climate mitigation strategies. Public health campaigns that integrate climate change mitigation with cancer prevention can yield synergistic benefits, fostering healthier behaviors and environments simultaneously.⁶⁴ The encouragement to continue a lifestyle with a healthy diet, like reduced red meat consumption, may benefit the cancer prevention strategies.⁶⁵ This integrated approach maximizes public health impact by addressing multiple goals with single, mutually reinforcing interventions, highlighting the powerful potential of interdisciplinary collaboration in the face of interconnected global challenges.