Review Article •International Open Medical Journal. 1(1):e202505  

Concerns Regarding the Widespread Application of Immune Checkpoint Inhibitors in Cancer Therapy

Authors

Taro Yamada^1#, Haruka Suzuki¹, Kenji Tanaka¹, Yuki Sato¹, Miho Nakamura^1*

Affiliations

1 Faculty of Medicine, The University of Tokyo, Tokyo, Japan

• Abstract

  The advent of immune checkpoint inhibitors (ICIs) represents a paradigm shift in oncology, offering unprecedented and durable clinical benefits across a wide spectrum of malignancies. By targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand (PD-L1), these therapies unleash the body’s own immune system to combat cancer. However, as ICIs transition from breakthrough therapy to a standard of care, their widespread application has unveiled a complex landscape of challenges. This review critically examines the most pressing concerns that temper the enthusiasm for these revolutionary drugs. We delve into the diverse and potentially life-threatening spectrum of immune-related adverse events (irAEs) and the evolving strategies for their management. We explore the formidable obstacles of primary and acquired resistance, dissecting the intricate tumor-intrinsic and microenvironmental factors that limit therapeutic efficacy. Furthermore, we analyze the ongoing, and often frustrating, quest for reliable predictive biomarkers beyond the current imperfect tools of PD-L1 expression, tumor mutational burden (TMB), and microsatellite instability (MSI). The significant risks and evidence gaps associated with treating special populations, such as patients with pre-existing autoimmune diseases, organ transplant recipients, and the elderly, are also discussed. Finally, we address the profound socioeconomic burden imposed by the high cost of ICIs, focusing on the concepts of financial toxicity and healthcare equity. By synthesizing evidence from the last five years, this review highlights the critical need for a more nuanced, personalized, and sustainable approach to fully realize the promise of cancer immunotherapy.

  Keywords: Immune Checkpoint Inhibitors, Cancer Therapy, Immune-Related Adverse Events (irAEs), Drug Resistance, Predictive Biomarkers, Financial Toxicity, Health Equity

  1. Introduction

  For decades, the pillars of cancer treatment were surgery, radiation, and chemotherapy. The introduction of targeted therapy in the early 2000s added a fourth pillar, but it was the clinical success of immune checkpoint inhibitors (ICIs) that established immunotherapy as the fifth, and arguably most revolutionary, pillar of modern cancer care [1, 2]. The initial approvals of ipilimumab (anti-CTLA-4) for metastatic melanoma, followed by the development of nivolumab and pembrolizumab (anti-PD-1), have burgeoned into a therapeutic class with broad indications, including non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), head and neck squamous cell carcinoma (HNSCC), bladder cancer, and mismatch repair-deficient (dMMR) solid tumors, among others [3, 4].

  The mechanism of ICIs is elegant in principle: they block inhibitory “checkpoint” pathways that tumors exploit to evade immune surveillance. This blockade effectively “releases the brakes” on T cells, enabling them to recognize and eliminate malignant cells [5]. This approach can lead to remarkably durable responses, with a subset of patients on long-term follow-up studies achieving survival plateaus that suggest a potential for functional cure—a concept rarely associated with advanced metastatic disease [6].

  However, this success story is accompanied by a growing list of significant concerns. The very mechanism that makes ICIs powerful—systemic immune activation—is also their greatest liability. Widespread clinical use has revealed that these therapies are not a panacea. A substantial portion of patients either do not respond at all (primary resistance) or develop resistance after an initial response (acquired resistance) [7]. Managing the unique and sometimes fatal toxicities, known as immune-related adverse events (irAEs), has become a subspecialty in itself [8]. Furthermore, accurately predicting which patients will benefit and which will suffer severe toxicity remains a major clinical challenge, as current biomarkers are fraught with limitations [9]. As indications expand to earlier-stage disease and patient populations with more comorbidities, questions of safety, risk-benefit balance, and cost-effectiveness become even more acute [10, 11]. This review will synthesize recent literature (2020-2025) to provide a comprehensive overview of these critical challenges that must be addressed to optimize the use of ICIs in the clinic.

  2. The Spectrum and Management of Immune-Related Adverse Events (irAEs)

  Unlike the predictable side effects of chemotherapy (e.g., myelosuppression, alopecia), irAEs are pleiotropic, unpredictable, and can affect virtually any organ system at any time during or after treatment [12]. They are a direct consequence of on-target immune activation, where T cells, no longer held in check, infiltrate and cause inflammatory damage to healthy tissues.

  2.1. Diverse Clinical Manifestations and Severity

  The most common irAEs involve the skin (rash, pruritus), colon (colitis, diarrhea), and endocrine glands (hypothyroidism, hyperthyroidism, hypophysitis, adrenal insufficiency) [8]. While often low-grade, they can be severe and life-threatening. For instance, immune-mediated colitis can lead to bowel perforation, requiring emergency surgery [13]. Similarly, pneumonitis, while less common, carries a significant mortality rate if not promptly recognized and treated.

  More recently, with increasing use, awareness of rare but highly morbid irAEs has grown. Cardiovascular toxicities, particularly myocarditis, are a prime example. Though occurring in less than 1% of patients, ICI-associated myocarditis can be fulminant, with mortality rates approaching 50% [14, 15]. Neurological irAEs, such as meningoencephalitis, Guillain-Barré syndrome, and myasthenia gravis, are also rare but can result in permanent disability or death [16]. The diagnostic challenge is substantial, as these symptoms are often nonspecific and require a high index of suspicion and extensive workup to rule out other causes.

  2.2. Management Challenges and Long-Term Sequelae

  The cornerstone of irAE management is immunosuppression, typically with corticosteroids. Guidelines from major societies like ASCO and ESMO provide a framework for grading toxicity and initiating treatment [8, 12]. However, a significant minority of patients develop steroid-refractory irAEs, necessitating second-line immunosuppressants like the TNF-alpha inhibitor infliximab for colitis or mycophenolate mofetil for hepatitis [17]. The use of these potent agents raises concerns about abrogating the anti-tumor effect of the ICI and increasing the risk of opportunistic infections. Finding therapies that can quell organ-specific inflammation without blunting the systemic anti-cancer immune response is a critical area of research [18].

  A growing concern is the long-term sequelae of irAEs. While many toxicities resolve, some result in permanent organ dysfunction. For example, immune-mediated endocrinopathies, such as type 1 diabetes resulting from pancreatitis or permanent hypothyroidism from thyroiditis, often require lifelong hormone replacement therapy [19]. The long-term impact on quality of life and the healthcare costs associated with managing these chronic conditions are only now beginning to be understood as the cohort of long-term ICI survivors grows [20].

  3. The Conundrum of Therapeutic Resistance

  Despite impressive results, the reality is that the majority of patients do not respond to ICI monotherapy. Understanding the mechanisms of this primary (innate) and acquired (evolved) resistance is one of the most urgent priorities in immuno-oncology.

  3.1. Mechanisms of Primary Resistance

  Primary resistance occurs when the tumor is inherently non-responsive to ICI therapy from the outset. The mechanisms are broadly categorized into tumor-intrinsic factors and deficiencies in the tumor microenvironment (TME) [7, 21].

  A key requirement for ICI efficacy is an immunologically “hot” or T-cell-inflamed TME. Tumors lacking T-cell infiltration, termed “cold” tumors, are often unresponsive [22]. This can be due to several factors:

  • Low Neoantigen Burden: Tumors with few mutations may not produce sufficient “non-self” peptides (neoantigens) to be recognized by T cells.
  • Defective Antigen Presentation: For T cells to see neoantigens, they must be processed and presented by the major histocompatibility complex (MHC). Mutations in genes involved in this machinery, such as B2M, are a well-described mechanism of immune evasion and ICI resistance [23].
  • Inhibitory TME: Even if T cells can infiltrate the tumor, their function can be suppressed by a host of other cells and factors. Regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and cancer-associated fibroblasts (CAFs) all create a deeply immunosuppressive milieu that can render anti-PD-1/PD-L1 therapy ineffective [7, 24].

  3.2. Mechanisms of Acquired Resistance

  Acquired resistance is a more vexing problem, where a patient’s tumor initially shrinks but then begins to grow despite continued treatment. This reflects a process of immunoediting and tumor evolution under the selective pressure of therapy [25]. Tumors can evolve to lose the specific neoantigens that were being targeted by T cells. Alternatively, they can develop new ways to suppress the immune response by upregulating alternative inhibitory checkpoints, such as TIM-3, LAG-3, and VISTA [26]. The development of therapies targeting these alternative checkpoints is a major focus of current drug development, leading to the recent approval of a LAG-3 inhibitor in combination with an anti-PD-1 antibody [27].

  4. The Quest for Predictive Biomarkers

  The ideal biomarker would accurately identify responders, non-responders, and those at high risk for severe toxicity before treatment begins. Unfortunately, the current tools are far from perfect.

  4.1. Limitations of Current Biomarkers

  • PD-L1 Expression: PD-L1 protein expression on tumor cells or immune cells, as measured by immunohistochemistry (IHC), is the most widely used biomarker. However, its predictive value is inconsistent. Some patients with PD-L1-negative tumors respond, while many with PD-L1-positive tumors do not [9]. This is due to the dynamic regulation of PD-L1, significant intratumoral heterogeneity, and a lack of standardization across different antibody clones and scoring systems [28].
  • Tumor Mutational Burden (TMB): TMB, a measure of the number of mutations per megabase of DNA, was once a promising pan-cancer biomarker. The rationale is that a higher TMB leads to more neoantigens and a greater likelihood of an immune response. While TMB-High status is associated with response in some cancers like NSCLC and bladder cancer, its utility has been questioned in others, and it failed to show a benefit in some key prospective trials, leading to a re-evaluation of its role [29]. Standardization of TMB testing also remains a major hurdle.
  • Mismatch Repair Deficiency (dMMR)/Microsatellite Instability-High (MSI-H): This is perhaps the most successful pan-cancer biomarker to date. Tumors with dMMR/MSI-H have a faulty DNA repair system, leading to extremely high TMB and robust responses to ICIs. However, this only applies to a small fraction of cancers, limiting its broad applicability [4].

  4.2. Emerging and Novel Biomarkers

  The future of biomarker discovery lies in more integrated, multi-omic approaches.

  • The Gut Microbiome: A fascinating body of research has demonstrated that the composition of the gut microbiome can profoundly influence systemic immunity and patient responses to ICIs [30]. Certain bacterial species are associated with enhanced efficacy, while others are linked to resistance and toxicity. This opens the possibility of using microbial signatures as biomarkers or even modulating the microbiome to improve outcomes [11].
  • Circulating Tumor DNA (ctDNA): Analyzing ctDNA from a simple blood draw (“liquid biopsy”) offers a non-invasive way to assess TMB and monitor tumor dynamics. A rapid decrease in ctDNA levels after starting ICIs can be an early indicator of response, while a rise can signal acquired resistance long before it is visible on imaging [31].
  • Advanced Imaging and Gene Expression Profiling: Techniques like multiplex immunofluorescence allow for the spatial characterization of the TME, revealing the location and interaction of different immune cell subsets. This provides a much richer picture than simple PD-L1 staining [32]. Similarly, RNA sequencing to identify immune-related gene expression signatures holds promise for creating more robust predictive models [22].
  5. Navigating Treatment in Special Populations

  Pivotal clinical trials for ICIs have traditionally enrolled a select, relatively healthy patient population. This has created a significant evidence gap for “real-world” patients who are often older, have more comorbidities, or have conditions that could be exacerbated by immunotherapy.

  • Patients with Pre-existing Autoimmune Disease: This group, representing up to 25% of the general population, was almost universally excluded from early trials due to the theoretical risk of severe disease flares. Retrospective data now suggest that while many of these patients can be treated safely, they face a significantly higher risk of both flares of their underlying condition and other severe irAEs, requiring careful multidisciplinary management [33].
  • Organ Transplant Recipients: For solid organ transplant recipients who develop cancer, ICIs pose a grave risk of inducing acute allograft rejection, which can be fatal or result in graft loss. The decision to use an ICI in this population involves a complex and often difficult risk-benefit calculation [34].
  • Elderly Patients: While age itself does not appear to be a contraindication, elderly patients (≥75 years) often have a higher burden of comorbidities, polypharmacy, and reduced physiological reserve, which may increase their susceptibility to severe irAEs. Tailoring treatment and supportive care for this growing demographic is crucial [35].
  6. The Socioeconomic Burden: Financial Toxicity and Healthcare Equity

  Beyond the clinical challenges, the widespread use of ICIs has created a formidable socioeconomic crisis. These drugs are among the most expensive medications in history, with annual costs per patient frequently exceeding $150,000 [36].

  This high cost generates “financial toxicity,” a term describing the direct and indirect financial distress experienced by patients and their families. High co-pays, deductibles, and loss of income can lead to debt, bankruptcy, and immense psychological stress [37]. Worryingly, financial toxicity is linked to poorer clinical outcomes, as patients may be forced to ration or discontinue life-saving treatment due to cost [38].

  On a macro level, the cost of ICIs places an enormous strain on healthcare systems worldwide, raising profound questions about sustainability and equity. Access to these transformative therapies can be limited by insurance coverage, national healthcare budgets, and socioeconomic status, creating disparities in cancer outcomes between and within countries [39, 40]. The challenge for society is to balance rewarding pharmaceutical innovation with ensuring that these life-extending drugs are accessible and affordable for all who might benefit.

  7. Conclusion

  Immune checkpoint inhibitors have fundamentally altered the prognosis for many patients with advanced cancer, offering hope where little existed before. However, the initial euphoria has matured into a more sober appreciation of the significant challenges that accompany their widespread use. The management of complex and potentially permanent irAEs, the pervasive problem of therapeutic resistance, the lack of definitive predictive biomarkers, and the immense socioeconomic burden represent formidable hurdles.

  The path forward is clear: the era of “one-size-fits-all” immunotherapy must give way to a more personalized approach. Future research must focus on several key areas:

  1. Developing Novel Therapies: Creating strategies to overcome resistance through rational combination therapies (e.g., ICI + targeted therapy, ICI + other immunomodulators) and developing safer treatments that can manage irAEs without compromising anti-tumor efficacy.
  2. Validating Better Biomarkers: Moving beyond single-analyte biomarkers to integrated, multi-modal signatures that incorporate genomics, transcriptomics, proteomics, and microbiome data to create a holistic “immune fitness” score for each patient.
  3. Designing Smarter Clinical Trials: Including more diverse and representative “real-world” populations in clinical trials to generate the evidence needed to guide treatment in special populations.
  4. Addressing Value and access: Fostering dialogue and policy changes among all stakeholders—pharmaceutical companies, payers, providers, and policymakers—to address the unsustainable cost of therapy and ensure equitable access.

  By tackling these challenges head-on, the medical community can continue to build on the revolutionary success of ICIs, refining their use to maximize benefit, minimize harm, and extend their life-saving potential to more patients in a sustainable and equitable manner.

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  Publication Dates
•  Publication in this collection
• 07 July 2025
• Date of issue
  • 2025
  • History
  • Received 30 March2025
  •  Accepted 25 June 2025