The impact of chronic comorbidities on cancer immunoediting: challenges and opportunities for immunotherapies

Immune surveillance is a central function of the immune system that prevents tumor initiation and progression. This process depends on the coordinated activity of innate and adaptive immune responses to recognize and eliminate transformed cells. However, pathological conditions can disrupt immune cell functions, impair immune surveillance, and facilitate tumor immune evasion. Chronic comorbidities, including obesity, type 2 diabetes mellitus (T2DM), non- alcoholic fatty liver disease (NAFLD/NASH), and cardiovascular disease (CVD), are increasingly prevalent among cancer patients and significantly influence tumor-immune interactions. These conditions promote systemic low-grade inflammation, metabolic alterations, immune dysfunction, T cell exhaustion, impaired antigen presentation, and the establishment of tolerogenic tissue microenvironments. Despite their relevance, comorbidities are often underrepresented in preclinical cancer models and insufficiently considered when assessing therapeutic responses. Emerging evidence suggests that chronic comorbidities modulate the efficacy and toxicity of immunotherapies that rely on immune activation. Integrating clinically relevant comorbidities into preclinical cancer models for the development of novel therapeutic strategies will be essential to improve immunosurveillance, limit tumor escape, and optimize personalized cancer immunotherapy outcomes.