Host-related Determinants of Response to Immunotherapy in Non-small Cell Lung Cancer: The Interplay of Body Composition, Metabolism, Sex and Immune Regulation.

Obesity is associated with paradoxical improvement in ICI outcomes in NSCLC, a phenomenon termed the 'obesity paradox.'

• The obesity paradox appears inconsistent across tumor types and may reflect disease-specific nutritional and immunological profiles.
• Obesity may modulate ICI outcomes through alterations in immune cell function and systemic inflammatory state.
• The relationship between BMI and ICI efficacy is not uniform and differs depending on the cancer type studied.

Sarcopenia is identified as a host-related factor that may negatively modulate ICI outcomes in NSCLC.

• Sarcopenia represents an altered body composition parameter distinct from obesity that affects anti-tumor immunity.
• Advances in cross-sectional imaging are refining the characterization of sarcopenia's impact on host-tumor-immune interactions.
• Sarcopenia is grouped alongside obesity as a body composition variable influencing immunotherapy efficacy.

Metabolic disorders including type 2 diabetes and dyslipidemia can promote chronic inflammation and immune exhaustion, potentially dampening ICI activity in NSCLC.

• Type 2 diabetes and dyslipidemia are specifically identified as metabolic comorbidities that negatively influence immunotherapy efficacy.
• These conditions promote chronic inflammation and immune exhaustion as the mechanistic pathway by which they affect ICI activity.
• Metabolic disorders are considered host-related determinants that shape anti-tumor immunity.

Sex is identified as a host-related determinant that influences immune regulation and shapes response to ICIs in NSCLC.

• Sex differences in immune regulation are recognized as contributing to differential ICI outcomes.
• Sex is grouped alongside body composition and metabolic comorbidities as integral host-related factors affecting immunotherapy.
• The review addresses sex as part of the dynamic continuum linking metabolism, body composition, systemic inflammation, and immune regulation.

Systemic inflammation is a key host-related determinant that shapes anti-tumor immunity and affects immunotherapy efficacy in NSCLC.

• Systemic inflammation is identified as an integral component of host-related factors influencing ICI outcomes.
• Chronic inflammation driven by metabolic comorbidities is linked to immune exhaustion that may dampen ICI activity.
• Systemic inflammation is part of a dynamic continuum with metabolism, body composition, and immune regulation.

Advances in cross-sectional imaging and molecular profiling are providing novel predictive insights into host-tumor-immune interactions in NSCLC.

• Cross-sectional imaging is specifically cited as a method refining characterization of body composition parameters such as sarcopenia.
• Molecular profiling is identified alongside imaging as a tool for better understanding host-related determinants of ICI response.
• These advances are framed as enabling more precise patient stratification for immunotherapy.

NSCLC is described as a biologically and clinically heterogeneous disease in which tumor-intrinsic and host-related factors both influence ICI outcomes.

• Host-related factors reviewed include body composition, metabolic comorbidities, sex, and systemic inflammation.
• Clinical outcomes from ICIs are influenced by these host-related factors in addition to tumor-intrinsic characteristics.
• The interplay of these factors is framed as an opportunity for personalized immunotherapy strategies.