Lipidomics reveals biomarkers of the efficacy of first-line ICIs therapy combined with chemotherapy in NSCLC

Immune checkpoint inhibitors (ICIs) plus chemotherapy have become the first-line standard therapy for patients with the gene-negative advanced non-small cell lung cancer (NSCLC). There is a lack of reliable biomarkers to predict treatment outcomes. This study aimed to identify relevant lipids that can predict treatment outcomes in NSCLC patients receiving first-line ICIs plus chemotherapy via lipidomics. Plasma samples were collected from Forty-nine patients with stage IIIB/IV NSCLC before the start of treatment, and patients were categorized into a long-term benefit group (progression-free survival [PFS] < 12 months) and a short-term benefit group (PFS ≥ 12 months). We identified13 lipids (FA-18:0, FA-18:2, FA-15:0, PS-36:3, PE-P-34:2, LPC-18:0, FA-20:3, LPI-18:1, LPC-14:0, PI-40:4, PE-O-34:2, FA-20:4, FAHFA-37:5) to predict the therapeutic efficacy of ICIs plus chemotherapy with high specificity and sensitivity We further investigated the role of linoleic acid (LA) (FA-18:2), a pivotal lipid involved in immune regulation, in animal and cellular models and explored its potential in enhancing NSCLC immunotherapy. Our results showed that LA can assist PD-1 inhibitors in exerting immune anti-tumor effects, slowing down tumor growth in mouse models, and suppressing the expression of PD-L1 proteins in both Lewis cells and tumor tissues. This study found that lipids were important biomarkers for predicting the efficacy of first-line ICIs plus chemotherapy in NSCLC patients, of which LA is an important adjuvant therapy for immune response.