Body mass index and dyslipidemia influence responses to anti-PD-1 immunotherapy in colorectal cancer

BACKGROUND: Obesity is one of the primary risk factors for colorectal cancer (CRC) development, but the impact of obesity on therapeutic responses to anti-programmed cell death protein 1 (PD-1) immunotherapy in CRC remains unclear. This retrospective study investigates relationships between body mass index (BMI), dyslipidemia, and clinical characteristics in immune checkpoint inhibitors (ICIs)-treated CRC patients, while analyzing associated metabolic variations. METHODS: Progression-free survival (PFS) was assessed in CRC patients receiving anti-PD-1 therapy, categorized by BMI and dyslipidemia status. Comprehensive lipidomic profiling was performed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to identify metabolic mechanisms underlying therapeutic responses. RESULTS: = 0.001). Multivariate analysis confirmed BMI as an independent prognostic factor for PFS. Moreover, patients with dyslipidemia exhibited extended PFS. Additionally, lipidomic analysis revealed differential pre-treatment levels of phosphatidylcholine (PC), phosphatidylethanolamine-ether (PE-O) and carnitine between the recurrence (R) and non-recurrence (NR) groups, accompanied by an enrichment trend in glycerophospholipid metabolism. CONCLUSION: Our findings show that obesity correlates with enhanced ICIs efficacy in CRC patients, potentially mediated through glycerophospholipid metabolic reprogramming. Furthermore, this association is more pronounced in the janus kinases 1/2 (JAK1/2) and β2-microglobulin (B2M) wild-type subgroup. These results support the potential utility of BMI as a predictive biomarker and highlight the need for further exploration of lipid-modulating combination therapeutic strategies.