Paradoxical effects of adiposity and inflammation on immunotherapy efficacy in gastric cancer: novel insights from real-world data.

Background: Emerging studies suggest obesity may improve PD-1/PD-L1 inhibitor efficacy, correlating with prolonged survival, known as the 'obesity paradox'. However, the impact of this paradox and obesity-related chronic inflammation on immunotherapy for advanced gastric cancer (AGC) has not received sufficient research.

Methods: Between January 2018 and December 2021, patients receiving neoadjuvant therapy were categorized into two groups: combined immunotherapy (ICIs, n = 173) and neoadjuvant chemotherapy (NAC, n = 126). Visceral (VATI) and subcutaneous adipose tissue index (SATI) were obtained from pre-treatment CT images. The systemic immune-inflammation index (SII) was calculated as platelet count multiplied by the neutrophil-to-lymphocyte ratio.

Results: The median age of patients was 64 years (IQR 56-69), with 219 (73.2%) males and 80 (26.8%) females. In the ICIs group, the VATI-High group showed significantly higher 3-year overall survival (OS) (p = 0.010) and disease-free survival (DFS) (p = 0.029). Similar results were observed in the SATI analysis (p < 0.05). Conversely, OS (p = 0.040) and DFS (p = 0.039) were significantly lower in the SII-High group. Both VATI and SATI were independent protective factors for OS and DFS, but the effect disappeared after adjustment for SII. SII was associated with poorer OS and DFS, even after adjustment for VATI and SATI. No significant differences were observed in the analysis of the NAC group.

Conclusions: Elevated adiposity indices (VATI/SATI) and low SII correlate with survival benefit in ICI-treated AGC patients, and importantly, this paradoxical survival benefit is dependent on SII status. In contrast, no such benefit is observed in chemotherapy-alone cohorts.