The role of hormonal and nutritional biomarkers in predicting immune checkpoint inhibitor efficacy: current limitations and future prospects.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet durable benefit remains limited to selected patients. Established biomarkers, including PD-L1 expression, tumor mutational burden, and microsatellite instability, remain predominantly tumor-centered and incompletely capture inter-individual variability. In this Perspective, we highlight systemic host physiology as an underappreciated determinant of the tumor microenvironment, ICI efficacy, and immune-related toxicity. We discuss how the hypothalamic-pituitary-adrenal axis, thyroid function, insulin signaling, nutritional status, micronutrients such as vitamin D and iron, emerging metabolic modulators, body composition, and the gut microbiome may influence T-cell activation, exhaustion, and myeloid-cell function. We also examine unresolved controversies, including the obesity paradox, the potential risk of GLP-1 receptor agonist-associated sarcopenia, and the lack of standardized biomarker thresholds and sampling protocols. To facilitate clinical translation, we outline a conceptual, hypothesis-generating spatiotemporal management framework integrating pre-treatment host profiling, peri-treatment metabolic and nutritional modulation, and post-treatment dynamic monitoring. Composite indices such as the Prognostic Immune and Nutritional Index, together with precise body-composition assessment, may improve risk stratification. However, host-directed interventions should be interpreted cautiously because current evidence remains heterogeneous and largely observational or preclinical. Prospective, multidisciplinary studies are required to validate these concepts and determine whether host-directed strategies can improve ICI efficacy while limiting immune-related toxicity.