Immune checkpoint inhibitors (ICIs) have significantly advanced cancer treatment by generating durable responses in many previously intractable malignant tumors (1). However, immune-related adverse events (irAEs) pose a substantial challenge to the clinical application of ICIs (2). Despite extensive research on the mechanisms of irAEs, there is still a lack of comprehensive analysis regarding the risk factors for irAEs across different patient populations, particularly in those with specific comorbidities (3). This gap hinders our understanding of how irAEs present in various groups, which in turn complicates the effective management of the benefit-risk ratio in ICIs therapy (4).

The prevalence of type 2 diabetes (T2DM), hypertension, and hyperlipidemia is rising annually, leading to an increase in comorbidities among cancer patients (5–8). Previous research has suggested that T2DM and hyperlipidemia may be potential immune-metabolic disorders that affect the activation, proliferation, and mobilization of immune cells (9, 10). Hyperglycemia and dyslipidemia are primary causes of metabolic homeostasis imbalance, which induces metabolic adaptations in immune cells and alters overall immune status. Additionally, studies have shown that hypertension can be a pro-inflammatory stimulus, increasing endothelial expression of cytokines and stimulating inflammation (11). These research findings consistently indicated that T2DM, hypertension, and hyperlipidemia have pro-inflammatory effects, revealing their regulatory roles in the systemic immune environment. This provides a theoretical basis for the association between these comorbidities and an increased risk of irAEs. However, there is currently a lack of clinical evidence to explore the specific associations between the occurrence of irAEs and T2DM, hypertension, and hyperlipidemia in patients undergoing ICIs therapy. Further research is necessary to clarify how these comorbidities affect the risk of irAEs in patients treated with ICIs, thereby providing stronger support for clinical decision-making and personalized treatment.

In this study, we retrospectively analyzed the clinical information of patients treated with ICIs. Our results indicate that the risk of irAEs is significantly increased in cancer patients with T2DM, hypertension, and hyperlipidemia. This finding not only provides new insights into the impact of comorbidities on the risk of irAEs but also lays a foundation for the clinical management of this specific patient population. By identifying high-risk patients, we can offer more targeted monitoring and intervention strategies for physicians, optimizing treatment outcomes and reducing the negative impact of irAEs on patients’ quality of life. Furthermore, the results of this study will encourage future prospective research to further explore the roles of these comorbidities in immunotherapy, ultimately providing scientific evidence to improve the overall prognosis of cancer patients.

In this study, we analyzed clinical data from 3,489 cancer patients treated with ICIs to evaluate the impact of comorbidities—specifically T2DM, hypertension, and hyperlipidemia—on the incidence of irAEs. Our findings revealed a significant association between these comorbidities and an increased risk of irAEs. Specifically, T2DM was linked to a 40% higher risk, hypertension to a 21% higher risk, and hyperlipidemia to a 62% higher risk of developing irAEs. T2DM primarily increased the risk of irAEs in lung cancer patients; meanwhile, hypertension and hyperlipidemia significantly elevated the risk of cardiac irAEs. These findings highlight the critical need to integrate the management of comorbidities into treatment plans for cancer patients receiving ICIs therapy. By identifying these conditions as significant contributors to the risk of irAEs, this study underscores the potential for personalized treatment strategies that optimize the balance between therapeutic efficacy and the minimization of irAEs. Incorporating regular monitoring and proactive management of these comorbidities could not only improve patient outcomes but also enhance the safety and long-term viability of ICIs therapy in diverse cancer populations.

irAEs can affect any organ, manifesting as localized signs of systemic immune dysfunction. Therefore, it is crucial in managing irAEs to consider other systemic diseases that may influence overall immune function (12, 13). Research on the association between comorbidities in cancer patients and irAEs is currently limited. Drawing from a large cohort of cancer patients treated with ICIs, our study identified a significant association between the presence of comorbidities, such as T2DM, hypertension, and hyperlipidemia, and an increased risk of developing irAEs. The biological mechanisms underlying these associations likely involve intricate interactions between metabolic pathways and immune responses (14). T2DM, hypertension, and hyperlipidemia often coexist with obesity (15–17). Increasing evidence indicates that obesity can induce chronic low-grade inflammation, activating inflammatory processes during adipose tissue expansion and persistently skewing the immune system towards a pro-inflammatory state ( Figure 4 ) (18, 19). A notable feature of obesity-related adipose tissue inflammation is an elevated number of macrophages and an altered ratio of M1 to M2 macrophages, which increases the release of pro-inflammatory factors (15, 20, 21). Obesity also heightens intestinal permeability, elevating circulating levels of lipopolysaccharides (LPS) derived from Gram-negative bacteria in the gut (22, 23). These gut-derived LPS can trigger inflammatory cascades by activating pattern recognition receptors such as Toll-like receptor 4 in adipocytes (24). Additionally, elevated levels of specific lipid species, such as free fatty acids or triglycerides, induced by diet or obesity, can contribute to inflammation (25). Obesity can also induce inflammation through distinct mechanisms such as hypoxia and increased mechanical pressure on adipocytes (19, 26, 27).

Vascular endothelial cells and myocardium are principal targets of pro-inflammatory pathways, which may explain the increased risk of cardiac irAEs associated with hypertension or hyperlipidemia (28–30). Notably, our research indicated a decreased risk of thyroid irAEs in cancer patients with concurrent hypertension, which may be the result of multiple mechanisms regulating immune response, metabolic effects, and drug action. Furthermore, our findings showed that T2DM significantly increased the risk of irAEs in lung cancer patients. Previous literature suggested that compared to non-diabetic patients, intestinal microbial diversity is generally reduced in diabetic patients (31). This reduction in microbial diversity not only disrupts the bidirectional crosstalk of the gut-lung axis, leading to respiratory hypersensitivity and overreaction, but also upregulates genes related to neutrophil and T cell activation, further increasing the risk of irAEs (32).

In this study, we focused on a large cohort of chronic disease patients in China and found that those with T2DM, hypertension, and hyperlipidemia undergoing ICIs therapy face a significantly higher risk of developing irAEs. This discovery enhances our understanding of how these chronic conditions influence irAEs and underscores the need for better prevention and management strategies in clinical practice. By identifying these chronic diseases as independent risk factors for irAEs, clinicians can now conduct more thorough risk assessments before initiating ICIs therapy, opening new opportunities for personalized treatment plans. Early interventions, such as optimizing blood glucose, blood pressure, and lipid levels, can help reduce the likelihood of irAEs and improve patient tolerance to ICIs therapy. Furthermore, the findings underscored the need for more frequent monitoring of chronic disease patients receiving ICIs therapy. Regular follow-up and early detection of potential adverse reactions allow clinicians to manage comorbidities more effectively, reducing the risk of irAEs. This proactive approach not only improves patient outcomes but also enhances the overall safety and effectiveness of ICIs therapy, ultimately maximizing its therapeutic benefits.

Several limitations should be noted. Firstly, the retrospective study design introduces the potential for selection bias and unaccounted confounding factors, such as race, lifestyle habits, and comorbidities, which may have influenced the results. Secondly, the single-center design limits the generalizability of the findings to broader and more diverse populations. Therefore, future multi-center prospective studies with larger sample sizes are needed to validate and strengthen these conclusions.

In summary, our study presented novel evidence that T2DM, hypertension, and hyperlipidemia markedly elevate the risk of irAEs among cancer patients treated with ICIs. These findings highlighted the critical need for thorough pre-treatment evaluation and diligent monitoring of these comorbidities in ICIs therapy recipients. Future prospective clinical studies and mechanistic investigations into the immune-regulatory roles of T2DM, hypertension, and hyperlipidemia are necessary to enhance the safety of ICIs therapy.