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Background The C-reactive protein (CRP) flare response, an indicator of early immune activation, has emerged as a promising and cost-effective biomarker for predicting response to immune checkpoint inhibitors (ICIs) across various tumor types. This study evaluates the utility of CRP dynamics as a tumor-agnostic biomarker and integrates systemic inflammatory markers with advanced multiparametric MRI metrics to uncover the biological mechanisms underlying the CRP flare phenomenon and its relationship with treatment response.Methods Patients were stratified into three groups based on CRP kinetics: (1) flare-responders, characterized by an initial doubling of baseline CRP followed by a decrease below baseline; (2) CRP responders, defined as patients with no flare increase but a CRP reduction of at least 30% below baseline and (3) CRP non-responders. Multiparametric MRI was performed at baseline, early (1–3 weeks), and intermediate (6–8 weeks) time points to assess tumor size and microstructural features, including cell density and vascularization. Clinical benefit and survival outcomes, including progression-free survival (PFS) and overall survival (OS), were analyzed using Kaplan-Meier curves and log-rank tests. Cox regression analyses were performed to identify independent predictors of clinical outcomes, while intergroup differences in MRI metrics were assessed using Wilcoxon rank-sum and Kruskal-Wallis tests.Results Among the 121 evaluable patients with solid tumors enrolled in the PREDICT trial, CRP flare-responders demonstrated significantly longer PFS (5.6 months) and OS (12.1 months) compared with responders (PFS: 3.4 months, OS: 8.0 months) and non-responders (PFS: 3.2 months, OS: 6.7 months; p=0.01 and p<0.01, respectively). Additionally, clinical benefit was achieved in 50% of flare-responders, compared with 13% of responders (p=0.05) and 23% of non-responders (p<0.01). Tumor growth was interrupted early after treatment initiation in CRP flare-responders, whereas non-responders exhibited marked increases in tumor size. In the pilot subset of 33 patients with MRI data, diffusion MRI revealed stable or increased apparent diffusion coefficient values in CRP flare-responders, indicative of reduced tumor cellularity just after 1–3 weeks of treatment.Conclusions This study highlights the potential of combining early CRP dynamics with non-invasive imaging metrics to identify ICI responders as early as 2 weeks after treatment initiation. By integrating systemic inflammatory biomarkers with MRI-derived insights into tumor size and microstructural changes, these findings optimize therapeutic strategies and advance understanding of immunotherapy-driven tumor dynamics.