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Background PD-1 checkpoint inhibitors achieve excellent therapeutic outcomes in the non-metastatic deficient mismatch repair (dMMR) and microsatellite instability-high (MSI-H) colorectal cancer (CRC). However, the problem of over-treatment still exists. We investigate the dynamic changes in serum proteins during immunotherapy in patients with non-metastatic dMMR/MSI-H CRC and explore potential biomarkers for predicting therapeutic response.Methods A total of 21 patients with non-metastatic dMMR/MSI-H CRC who received PD-1 inhibitor therapy were included in this study. Tumor response was assessed according to RECIST 1.1 criteria based on evaluations of computed tomography (CT), magnetic resonance imaging (MRI), and gastrointestinal endoscopy. All patients were classified into the complete response (CR) group and the non-complete response (non-CR) group. Serum samples were collected from these patients before and after immunotherapy and analyzed using Olink Proteomics.Results Following PD-1 inhibitor therapy, 15 patients (71.4%) achieved CR, while 6 patients (28.6%) achieved non-CR ( IDDF2026-ABS-0310 Figure 1(A-C)). Comparative analysis between pre- and post-treatment serum samples revealed increased expression of proteins and decreased expression of proteins following therapy (IDDF2026-ABS-0310 Figure 2(A)). Over-representation analysis indicated that the differentially expressed proteins after PD-1 inhibitor therapy were predominantly enriched in the PI3K-Akt signaling pathway, in addition to immune-related signaling pathways (IDDF2026-ABS-0310 Figure 2(B)). Notably, the protein levels of PDCD1, GDF2, ALCAM, SUSD2, DDC, FAP, KLK8, IL32, THY1 and ADGRG2 gradually increased during the course of immunotherapy, whereas IL6, NOS2, CXCL8, S100A12, COPB2 exhibited sustained upregulation (IDDF2026-ABS-0310 Figure 2(C,D)). Principal component analysis revealed significant differences in baseline protein profiles between the favorable response group and the poor response group prior to treatment initiation (IDDF2026-ABS-0310 Figure 3(A,B)). Among the differentially up-regulated and down-regulated expressed proteins, CNTN5, BPIFA2, GH2, IL7R, TNFSR12, AKR1C4, BPIFB2, NEEL, ROCR1, and FGF21 were significantly associated with favorable therapeutic responses and may serve as predictive biomarkers for CR (IDDF2026-ABS-0310 Figure 3(C,D)).Conclusions Our study demonstrated that nearly 70% of non-metastatic dMMR/MSI-H CRC patients achieved CR following PD-1 inhibitor therapy. Specific serum proteins may serve as predictive biomarkers for immunotherapy outcomes. Real-time dynamic monitoring of protein expression can provide timely indications of therapeutic efficacy, thereby helping to prevent overtreatment.Abstract IDDF2026-ABS-0310 Figure 1Abstract IDDF2026-ABS-0310 Figure 2Abstract IDDF2026-ABS-0310 Figure 3