Serum lipid profiling identified 56 baseline and 214 post-treatment differential lipids distinguishing complete response from progressive disease in dMMR/MSI-H CRC patients on anti-PD-1 therapy.
Does structural lipidomics profiling identify predictive biomarkers for anti-PD-1 treatment response in dMMR/MSI-H colorectal cancer patients?
Deep structural lipidomics using LC-PB-MS/MS can identify specific lipid signatures that stratify dMMR/MSI-H colorectal cancer patients by their response to anti-PD-1 therapy.
Lipidomics offers valuable insights for cancer research. Paternò–Büchi (PB) reaction-based LC-MS/MS enables precise lipid structural resolution at the C═C location level. Although mismatch repair-deficient or microsatellite instability-high (dMMR/MSI-H) status predicts anti-PD-1 response in colorectal cancer (CRC), nearly half of the patients do not benefit, underscoring the need for better biomarkers. Here, we applied sequential LC-MS, LC-MS/MS, and LC-PB-MS/MS to profile serum lipids from 58 dMMR/MSI-H CRC patients receiving anti-PD-1 treatment. The resulting lipidomic data were subsequently explored to identify predictive biomarkers for efficacy. We identified 814 glycerophospholipids, 285 of which were resolved at the C═C location level. Comparative analyses revealed 56 differential lipids between patients achieving complete response (CR) and progressive disease (PD) before treatment and 214 after therapy (p 1), most elevated in CR groups. Correlation and clustering patterns indicated coordinated lipid remodeling, and principal component analysis (PCA) demonstrated group separation at both the baseline and post-treatment. Key lipids associated with treatment response included PC (14: 0₁8: 2 (Δ9, Δ12) ), PG (31: 1), PI (39: 7), PG (41: 7), LPC (24: 0), PE (O-42: 9), PE (43: 5), PC (16: 0₂0: 5 (Δ5, Δ8, Δ11, Δ14, Δ17) ), LPE (18: 2 (Δ11, Δ14) ), and PG (16: 0₂0: 2) before treatment and PI (44: 1), PI (34: 1), PC (18: 1 (Δ11) ₂0: 2 (Δ8, Δ14) ), PI (44: 0), PG (42: 4), PC (O-16: 0/18: 1 (Δ10) ), PC (15: 0₁8: 1 (Δ10) ), PC (14: 0₁8: 1 (Δ9) ), PI (16: 0₁8: 1 (Δ15) ), and PC (16: 0₁6: 1 (Δ7) ) after treatment. Overall, LC-PB-MS/MS enables deep structural lipidomics, uncovering lipid signatures capable of stratifying dMMR/MSI-H CRC patients by therapeutic outcome. The identified lipid markers hold promise for monitoring treatment and for developing novel therapeutic strategies.
Tou et al. (2026) studied this question. Serum lipid profiling identified 56 baseline and 214 post-treatment differential lipids distinguishing complete response from progressive disease in dMMR/MSI-H CRC patients on anti-PD-1 therapy.
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