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

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. 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.

This study enrolled 142 CRC patients who completed ≥ 2 cycles of anti-PD-1 therapy. Patients with BMI ≥ 24 kg/m2 (overweight per Chinese criteria) showed significantly longer PFS compared to normal BMI counterparts (p = 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.

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.