Purpose of Review <p>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.</p> Recent Findings <p>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.</p> Summary <p>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.</p>