Host-related Determinants of Response to Immunotherapy in Non-small Cell Lung Cancer: The Interplay of Body Composition, Metabolism, Sex and Immune Regulation
Valentina Santo, Leonardo Brunetti, F. Pecci, M. Peroni, Giulia Barnini, Francesco Paoloni, Sebastiano Buti, Marcello Tiseo, Biagio Ricciuti, David James Pinato, Alessio Cortellini
Abstract
PURPOSE OF REVIEW: Non-small cell lung cancer (NSCLC) is a biologically and clinically heterogeneous disease. In addition to tumor-intrinsic characteristics, clinical outcomes from immune checkpoint inhibitors (ICIs) are influenced by a variety of host-related factors. This review aims to summarize current evidence on how body composition, metabolic comorbidities, sex, and systemic inflammation shape anti-tumor immunity and affect immunotherapy efficacy. RECENT FINDINGS: Emerging data suggest that altered body composition, including obesity and sarcopenia, may modulate ICI outcomes, giving rise to the so-called "obesity paradox", which appears inconsistent across tumor types and may reflect disease-specific nutritional and immunological profiles. Likewise, metabolic disorders such as type 2 diabetes and dyslipidemia can promote chronic inflammation and immune exhaustion, potentially dampening ICI activity. Advances in cross-sectional imaging and molecular profiling are refining the characterization of host-tumor-immune interactions and providing novel predictive insights. Host-related determinants play an integral role in shaping response to ICIs in NSCLC. A deeper understanding of the dynamic continuum linking metabolism, body composition, systemic inflammation, and immune regulation may enable more precise patient stratification and open opportunities for personalized immunotherapy strategies.