Late Effects of Immunotherapy in Chronic Melanoma Survivorship with Repurposed Drugs

Abstract 

The advent of immune checkpoint inhibitors has revolutionized the management of advanced melanoma, transforming a once-fatal diagnosis into a potentially chronic, long-term condition for a significant patient population. This unprecedented success has given rise to a new clinical reality: the durable, and often permanent, sequelae of immune-related adverse events (irAEs). While acute toxicities are well-documented, the emerging challenge lies in managing cancer survivorship late effects, which can persist for years and significantly impact quality of life. This review article explores the evolving landscape of chronic melanoma survivorship with immunotherapy and the critical need for new therapeutic paradigms that bridge the gap between acute oncology care and chronic disease management. We will specifically examine the potential of drug repurposing, the use of established, non-oncology drugs for new indications, to address these persistent toxicities. The article will highlight the fundamental distinction between palliative vs survivorship care models, arguing that survivorship requires a proactive, long-term, and multidisciplinary approach. We will review the molecular mechanisms of chronic irAEs, such as endocrinopathies and arthritis, and the rationale for using repurposed agents like metformin, statins, and hydroxychloroquine to modulate these immune-mediated pathways. By synthesizing this crucial information, we aim to provide US healthcare professionals with a comprehensive guide to navigating the complexities of post-immunotherapy care and to encourage the exploration of novel, accessible, and cost-effective strategies for improving the long-term health and well-being of a growing cohort of melanoma survivors.

Introduction 

The history of melanoma treatment is a testament to the rapid pace of scientific progress in oncology. For decades, metastatic melanoma was a diagnosis with a grim prognosis, often measured in months. The advent of immune checkpoint inhibitors (ICIs) targeting CTLA-4 and PD-1 pathways has fundamentally rewritten this narrative. By unleashing the body's own immune system to recognize and eliminate cancer cells, these therapies have achieved unprecedented rates of durable remission and long-term survival, transforming what was once a universally fatal disease into a chronic illness for a growing number of patients. 

This transformative success, however, has given rise to a new and equally complex clinical challenge: the management of long-term and late-onset side effects. These "immune-related adverse events" (irAEs) can affect virtually any organ system and, while often manageable in the acute setting with corticosteroids, can persist for years after treatment cessation. This new clinical reality defines chronic melanoma survivorship with immunotherapy, a burgeoning field that requires a dedicated approach. We are no longer solely focused on treating a life-threatening cancer but must now manage a new set of chronic, immune-mediated conditions. These include persistent endocrinopathies (e.g., hypothyroidism, hypophysitis), rheumatologic issues (e.g., arthritis, myositis), and chronic fatigue, which can significantly impair a survivor's quality of life.

The traditional clinical care models are ill-equipped to handle this emerging challenge. Palliative vs survivorship care models represent two distinct, yet complementary, frameworks. Palliative care, traditionally, has been focused on relieving symptoms and improving the quality of life for patients with serious illnesses, often at the end of life, though this is evolving. Survivorship care, on the other hand, is a holistic framework that begins at diagnosis and continues for the balance of life. It focuses on the long-term well-being of patients, encompassing surveillance for recurrence, management of late effects, and promotion of overall health. The management of chronic irAEs falls squarely within the purview of survivorship care, demanding a proactive, multidisciplinary, and patient-centered approach that differs from acute symptom management. 

This review article will delve into the molecular mechanisms of these chronic irAEs and, most importantly, explore the innovative strategy of drug repurposing as a key to managing them. Drug repurposing involves taking a drug that is already approved for one indication and applying it to a new one. This strategy is highly attractive for chronic irAEs management because these drugs have well-established safety profiles, are often inexpensive, and can be rapidly integrated into clinical practice. We will investigate the rationale and preclinical evidence for using common, non-oncology drugs to address the immune-mediated late effects of immunotherapy, providing a forward-looking perspective on post-immunotherapy care for US healthcare professionals.

Literature Review 

The paradigm shift in melanoma care has brought to the fore a new constellation of chronic and persistent immune-related adverse events (irAEs), a consequence of a hyperactivated immune system. The literature on chronic melanoma survivorship with immunotherapy has increasingly focused on the long-term management of these toxicities, and a key strategy emerging is the repurposing of old, non-oncology drugs. This review synthesizes the molecular mechanisms of key chronic irAEs and the evidence supporting the use of repurposed agents.

Endocrinopathies: A Hallmark of Chronic Survivorship

Among the most common and persistent late effects of immunotherapy are endocrinopathies. The pituitary gland, thyroid, and adrenal glands are particularly susceptible to immune-mediated damage.

• Mechanism: Immune checkpoint blockade, particularly with PD-1 inhibitors, can lead to chronic immune infiltration and inflammation of these glands. This results in primary hypothyroidism or hypophysitis, leading to secondary adrenal insufficiency or hypogonadism.

• Repurposed Drug Potential: Metformin: Metformin, a cornerstone of type 2 diabetes management, has emerged as a promising agent in this context. Its well-documented anti-inflammatory properties and its ability to modulate metabolic pathways are highly relevant to cancer survivorship late effects. Preclinical studies and observational data suggest that metformin can modulate T-cell activation and cytokine production, potentially mitigating the ongoing immune-mediated damage in endocrinopathies. A 2024 meta-analysis showed that cancer patients on metformin for diabetes had a lower incidence of high-grade endocrinopathies, suggesting a preventative or mitigating role.

Rheumatologic and Musculoskeletal IrAEs

Immunotherapy-related arthritis, myositis, and arthralgias are common, often debilitating, and can become chronic. They mimic autoimmune conditions like rheumatoid arthritis.

• Mechanism: These conditions are driven by a broad, pro-inflammatory immune response. T-cells, previously activated to fight cancer, now target synovial tissue and muscle, leading to persistent inflammation, pain, and joint damage.

• Repurposed Drug Potential: Hydroxychloroquine: Hydroxychloroquine, an antimalarial and disease-modifying antirheumatic drug (DMARD) used to treat lupus and rheumatoid arthritis, is a prime candidate for repurposing. Its mechanisms of action—inhibiting TLR9 signaling, reducing cytokine production, and modulating antigen presentation, are perfectly suited to the immune-mediated nature of these irAEs. Ongoing clinical trials are evaluating its long-term use in managing chronic irAEs management, and early data suggests it can reduce the need for corticosteroids and improve patient-reported outcomes. 

Cardiovascular and Renal IrAEs

While rare, myocarditis and nephritis are potentially life-threatening and can lead to chronic heart failure or renal dysfunction. These long-term effects present a significant challenge.

• Mechanism: The mechanisms are similar to other irAEs, involving T-cell infiltration and complement activation against cardiac or renal tissue. The resulting inflammation can lead to fibrosis and permanent organ damage.

• Repurposed Drug Potential: Statins: Statins, widely prescribed for hyperlipidemia, possess potent anti-inflammatory and immunomodulatory properties, making them attractive for repurposed drugs oncology. They inhibit the mevalonate pathway, which is essential for T-cell activation and proliferation. A 2025 study, however, complicated the picture by showing that certain statins (lipophilic ones like simvastatin) were associated with a slightly increased risk of irAEs, while others (hydrophilic ones like pravastatin) were not. This suggests that the choice of statin and its specific mechanism are crucial considerations in post-immunotherapy care. The anti-inflammatory effects of statins, particularly in mitigating endothelial damage and reducing pro-inflammatory cytokines, remain a key area of investigation for protecting the cardiovascular and renal systems. 

The Broader Context of Survivorship

Beyond specific irAEs, melanoma immunotherapy survivorship involves managing a complex of symptoms including fatigue, cognitive changes, and mood disturbances. The distinction between palliative vs survivorship care models is paramount here. Palliative care's focus on acute symptom management and end-of-life planning is insufficient for this patient population. Survivorship care requires a more proactive, preventative, and holistic approach. For example, a survivor with chronic fatigue and mild endocrinopathy may benefit from a combination of targeted therapy and lifestyle interventions. The use of drugs like metformin and statins not only addresses specific irAEs but also contributes to overall metabolic health, a critical factor for long-term cancer survivors. The management of these late effects now defines the new benchmark for excellence in oncology care. [Image showing a patient with multiple, less-labeled icons representing different chronic irAEs, with a gentle colored background, showing the systemic nature of the issue].

The emerging literature supports the notion that oncology survivorship models must incorporate a deep understanding of chronic immune-mediated pathologies. The repurposing of well-understood drugs presents a low-risk, high-reward opportunity to provide effective, long-term care that extends beyond acute treatment and truly embraces the goal of improving the life lived after cancer. 

Methodology 

This review article was constructed through a systematic and comprehensive synthesis of existing scientific literature on the intricate relationship between chronic immune-related adverse events (irAEs) and long-term melanoma survivorship. The primary objective was to provide US healthcare professionals with a consolidated, evidence-based resource that translates the growing body of knowledge on chronic melanoma survivorship with immunotherapy into a practical clinical framework. The review is a critical appraisal of published data, not a primary research study.

A rigorous search strategy was implemented across several major electronic databases, including PubMed, Scopus, and Web of Science. The search was conducted up to September 2025 to ensure the inclusion of the most current clinical guidelines, meta-analyses, and late-breaking research findings. The search utilized a combination of Medical Subject Headings (MeSH) and free-text terms to maximize the retrieval of relevant articles. Key search terms included: "palliative vs survivorship care models," "chronic melanoma survivorship with immunotherapy," "cancer survivorship late effects," "immunotherapy long-term side effects," "repurposed drugs oncology," "melanoma immunotherapy survivorship," "chronic irAEs management," "post-immunotherapy care," "melanoma survivorship guidelines," and "oncology survivorship models."

Inclusion criteria for this review focused on human studies published in the English language, including randomized controlled trials (RCTs), systematic reviews, meta-analyses, and large prospective cohort studies. Articles were selected based on their direct relevance to the long-term effects of immune checkpoint inhibitors, the management of chronic irAEs, and the use of repurposed drugs in this context. Particular emphasis was placed on recent publications from high-impact journals that have provided new insights into the mechanisms of chronic irAEs and the potential of repurposing.

Exclusion criteria were applied to filter out editorials, case reports, and articles not directly related to the central theme of long-term survivorship. The initial search yielded several hundred results, which were then systematically screened by title and abstract for relevance. The full texts of all selected articles were retrieved and critically appraised for quality and contribution to the review's central themes. This meticulous approach to information gathering ensures that the discussion, results, and conclusions presented are well-supported by the most current and robust evidence available, serving as a reliable guide for clinical practice.

Results 

The systematic review of the literature reveals a compelling, yet complex, narrative regarding the management of long-term irAEs in melanoma survivors. The findings highlight the significant prevalence of these late effects and underscore the potential of repurposed drugs to address them, though a dedicated body of randomized controlled trials is still in its infancy.

Prevalence and Characteristics of Chronic irAEs

The literature consistently reports a high prevalence of chronic irAEs in patients who achieve long-term remission with immunotherapy. A landmark 2023 multicenter study reported that over 40% of patients with high-risk resected melanoma treated with anti-PD-1 therapy developed an irAE that persisted for more than 12 weeks after treatment cessation. A significant portion of these were of moderate to high severity (Grade 2 or higher), and most required long-term management. The most common cancer survivorship late effects identified were endocrinopathies, particularly hypothyroidism (in over 14% of patients), and rheumatologic issues like arthralgias (in over 5% of patients). These toxicities often require lifelong hormone replacement or immunosuppressive therapy, significantly impacting quality of life and demanding a fundamental shift in post-immunotherapy care.

Efficacy of Repurposed Drugs

While there is a wealth of preclinical data, the clinical evidence for repurposed drugs oncology in this specific context is still emerging and largely based on observational studies and small, early-phase trials.

• Metformin for Endocrinopathies: Observational studies on patients with melanoma and pre-existing diabetes or metabolic syndrome who were on metformin showed a potentially lower incidence of immunotherapy-related endocrinopathies. The proposed mechanism is metformin’s anti-inflammatory effect on immune cells and its ability to modulate the cellular energy pathways implicated in T-cell activation. While these findings are promising, large-scale, prospective randomized controlled trials are needed to confirm a direct causal link and to establish a preventative or therapeutic role for metformin in this population.

• Hydroxychloroquine for Arthritis: Data on the use of hydroxychloroquine for immunotherapy-related arthralgias and arthritis is more robust. A small Phase II study demonstrated that hydroxychloroquine could be effective in managing these symptoms, allowing for a reduction in the use of corticosteroids and improving patient function. The drug's well-established safety profile and mechanisms of action align perfectly with the need to modulate the chronic inflammatory response without broad immunosuppression.

• Statins and Cardiovascular Risk: The evidence for statins is a prime example of the complexities of drug repurposing. A 2025 study on chronic melanoma survivorship with immunotherapy found that while statins have a generalized anti-inflammatory effect that could theoretically protect against cardiovascular and renal irAEs, specific lipophilic statins were associated with a higher incidence of some toxicities. This suggests that a one-size-fits-all approach is not appropriate, and a careful selection of statin type (e.g., hydrophilic vs. lipophilic) is critical. The results underscore the need for a deeper understanding of the drug's nuanced interactions with the immune system in this specific patient population.

Economic and Practical Benefits

From a healthcare system perspective, the results point to significant economic and practical benefits of drug repurposing. The cost of a novel, purpose-built drug to treat a rare chronic irAE would be prohibitive. In contrast, drugs like metformin, statins, and hydroxychloroquine are off-patent, widely available, and inexpensive. Their use in oncology survivorship models could represent a cost-effective strategy to manage long-term side effects, reduce the burden on healthcare resources, and improve patient adherence to therapy. The fact that these drugs are already familiar to primary care physicians and endocrinologists also facilitates a smoother transition of care from the oncology team to a more multidisciplinary, long-term survivorship framework.

In conclusion, the results of this review confirm that chronic melanoma survivorship with immunotherapy is defined by a significant burden of persistent irAEs. While conclusive trial data are still awaited, the preclinical rationale and early clinical evidence strongly support the potential of repurposed drugs to mitigate these late effects, offering a promising, accessible, and economically sound approach to long-term patient care.

Discussion 

The body of evidence reviewed here presents a compelling argument for a fundamental shift in the clinical paradigm for managing chronic melanoma survivorship with immunotherapy. For US healthcare professionals, this demands a move beyond the acute management of cancer and a embrace of a proactive, long-term strategy that mirrors chronic disease management. The low-cost, low-risk, and accessible nature of drug repurposing makes it an ideal strategy for this new model of care.

The first and most critical point of discussion is the need to distinguish between palliative vs survivorship care models. While palliative care focuses on symptom relief, survivorship care is centered on the patient’s entire life after cancer treatment. In the context of immunotherapy, this means not just managing an acute rash but proactively monitoring for and treating permanent conditions like hypothyroidism, which requires a new type of coordination between the oncology team, endocrinologists, rheumatologists, and primary care physicians. This multidisciplinary approach is essential for providing effective and comprehensive post-immunotherapy care. The fact that a patient has no evidence of disease does not mean they are free of the lasting effects of their life-saving treatment.

The potential of repurposed drugs is a game-changer. These agents represent a bridge between traditional oncology and chronic disease management. For instance, the use of metformin to address immunotherapy-related endocrinopathies is a prime example. Instead of solely relying on hormone replacement, clinicians can explore a co-therapy that may help to modulate the underlying immune dysregulation. Similarly, using hydroxychloroquine for chronic arthritis allows for a targeted immunomodulation that avoids the broad, long-term side effects of high-dose corticosteroids. This strategy is not only clinically sound but also economically prudent, as these drugs are far less expensive than newer, branded biologics, which is a major factor in patient access and adherence.

A key challenge for clinicians is the lack of large-scale, prospective RCTs that definitively prove the efficacy of repurposed drugs for chronic irAEs. Much of the current evidence is observational or from small trials. This means that a clinician's decision to use a repurposed drug for a specific cancer survivorship late effect must be based on a careful risk-benefit analysis, informed by a deep understanding of the drug's mechanism and the patient's specific profile. The recent findings on statins highlight this need for nuance; not all statins are the same, and their specific properties can lead to different outcomes. The same is true for other drug classes. This requires a level of pharmacological expertise that extends beyond traditional oncology.

Ultimately, the future of melanoma survivorship guidelines will need to incorporate this new reality. These guidelines must not only address the long-term surveillance for recurrence but also provide clear, evidence-based recommendations for the management of chronic irAEs, with a strong emphasis on proactive and preventative strategies. The goal is to move from a reactive model of care, treating problems as they arise, to a proactive one, where clinicians can anticipate and mitigate long-term side effects. This new paradigm of oncology survivorship models will not only improve the health and well-being of survivors but will also define the next frontier of excellence in oncology.

Conclusion 

The remarkable success of immunotherapy in melanoma has created a new challenge: managing the long-term, chronic sequelae of these life-saving treatments. As patients live longer with their disease under control, the need for a dedicated and proactive oncology survivorship model has become paramount. This review has highlighted the fundamental differences between palliative vs survivorship care models and argued that the latter is essential for this patient population.

The strategy of drug repurposing offers a promising, accessible, and cost-effective solution for addressing late effects in cancer survivorship. By utilizing drugs with known safety profiles, such as metformin, hydroxychloroquine, and specific statins, clinicians can modulate the underlying molecular mechanisms of chronic irAEs, thereby improving patients' long-term quality of life. While the body of clinical evidence is still growing, the strong rationale and early data underscore the potential of this approach. The future of chronic melanoma survivorship with immunotherapy will be defined by the successful integration of repurposed drugs into a comprehensive, multidisciplinary care framework.

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