Plasma Small Extracellular Vesicle-Derived GDF15 Predicts Resistance to PD-1/PD-L1-Based Therapy in Colorectal Cancer: A Pilot Study

Background Immune checkpoint inhibitors (ICIs) have markedly improved cancer treatment outcomes, but both intrinsic and acquired resistance remain major barriers, particularly in microsatellite stable (MSS) colorectal cancer (CRC). Growth differentiation factor-15 (GDF15) contributes to tumor immune evasion, yet its clinical significance as a non-invasive liquid biopsy marker for predicting immunotherapy response in CRC is still unclear. Methods In this pilot investigation, we explored plasma-derived small extracellular vesicles (sEVs) as a source of biomarkers. Plasma sEVs were isolated from 20 CRC patients receiving PD-1/PD-L1 blockade in combination with oxaliplatin-based chemotherapy. GDF15 expression at both the mRNA and protein levels was quantified in tumor tissue and circulating sEVs by qPCR and Western blotting. Transcriptomic profiling and pathway enrichment analyses were also conducted to elucidate relevant molecular processes. Results GDF15 levels were markedly higher in CRC tumor tissues and plasma sEVs compared to healthy controls. Baseline plasma sEV-GDF15 mRNA expression was significantly elevated in non-responders (stable/progressive disease, n = 12) relative to responders (complete/partial response, n = 8) (23.34 ± 9.32 vs. 5.25 ± 2.32; P < 0.01). Receiver operating characteristic (ROC) analysis demonstrated a strong ability to discriminate non-responders from responders, with an AUC of 0.864 (95% CI: 0.706–1.000). Transcriptomic data further indicated enrichment of immune-related and GDF15-associated pathways in high-GDF15 cases, providing mechanistic insights. Conclusions This pilot study highlights plasma sEV-derived GDF15 as a potential liquid biopsy marker for predicting resistance to ICI-based therapy in CRC. Our findings suggest that elevated sEV-GDF15 appears to be linked to unfavorable outcomes and immune-related mechanisms driving therapeutic resistance. These results warrant prospective validation in larger cohorts and underscore the potential of sEV-GDF15 for guiding clinical decisions and as a potential therapeutic target.