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Although immune checkpoint inhibitor (ICI) therapy is currently the standard of care in microsatellite-unstable (MSI) metastatic colorectal cancer (CRC), ICI therapy, alone or in combination with other therapies, is not a treatment approach in microsatellite-stable (MSS) CRC, which is present in 95% of patients. In this review, we focus on metabolic singularities-at the transcriptomic (either bulk or single cell), proteomic, and post-translational modification levels-that induce immunosuppression in cancer and specifically in MSS CRC. First, we evaluate the current efficacy of ICIs in limited and metastatic disease in MSS CRC. Second, we discuss the latest findings on the potential biomarkers for evaluating ICI efficacy in MSS CRC using strict REMARK criteria. Third, we review the current evidence on metabolic patterns in CRC tumors and immune cell metabolism to advance our understanding of metabolic crosstalk and to pave the way for the development of combination strategies to enhance ICI efficacy.

Introduction: Immune check-point inhibitors (ICI) were a major breakthrough in cancer care, but optimal patient selection remains elusive in most tumors., Methods: Overall 173 adult patients with metastatic solid tumors candidates to ICI in clinical trials at our Institution were prospectively recruited. Blood samples were collected at cycle 1 (C1D1) and 2 (C2D1) and until the occurrence of progressive disease (PD). C1D1 LIPI, RMH, PMHI, NLR, dNLR, PIPO and GRIm prognostic scores were calculated. The primary endpoint was identifying the best score to predict rapid PD (≤ 4 months) with ICI using logistic regressions accounting for tumor type, and receiving operators characteristics (ROC) with area under curve (AUC), accompanied by an extensive comparison of the score performances in the prediction of overall survival (OS), progression-free survival (PFS), overall response rates (ORR) and durable clinical benefit (DCB). Secondary objectives included describing study cohort outcomes and studying the association between the selected score at C1D1, C2D1 and its dynamics with OS and PFS., Results: C1D1 LIPI was the best predictor of rapid PD, OS and PFS, regardless of cancer type, compared to other scores. No score was associated to ORR and only RMH to DCB. Baseline LIPI detected three categories of patients with significantly different OS (p < 0.001) and PFS (p = 0.013). The same was observed at C2D1 for OS and PFS (both p = 0.020). Significant LIPI class shifts were observed in the overall population (p < 0.001), rapid progressors (p = 0.029) and non-rapid progressors (p = 0.009). Retaining a good LIPI or experiencing a shift towards a better prognostic class was associated to improved OS (p = 0.009) and PFS (p = 0.006). C2D1 LIPI, but not C1D1, remained significantly associated to rapid PD in multivariable analysis., Conclusions: LIPI may improve patient selection for ICI and guide treatment adjustments according to on-treatment dynamics in a pancancer context., Competing Interests: Declarations. Conflict of interest: J. García-Corbacho reports travel expenses from BMS and Pfizer and honoraria from Astra Zeneca, GSK, Lilly, Regeneron, Roche and Pfizer. L. Mezquita reports grants/research support from Amgen, Inivata, AstraZeneca and Gilead, honoraria/consultation fees from Roche, Takeda, Janssen and MSD, lectures and educational activities for Bristol-Meyers Squibb, Roche, Takeda, AstraZeneca, MSD, Radonova and Janssen, travel accommodation/expenses from Bristol-Meyers Squibb, Roche, Takeda, AstraZeneca and Janssen. F. Brasó-Maristany reports patent application (PCT/EP2022/086493, PCT/EP2023/060810, EP23382703 and EP23383369). N. Basté participated in advisory boards for Nanobiotix, Merck Serono, MSD, BioNtech, Roche, and BMS. T. Saurí served as a consultant at AstraZeneca, BMS, Roche, MSD, AMGEN, and Daiichi Sankyo and received lecture fees from BMS and MSD; B. Mellado reports research funding from Janssen, Roche, Bayer, and Pfizer; speakers’ bureau for Roche, Sanofi, Janssen, Astellas, Pfizer, Novartis, and Bristol-Myers Squibb; and travel and accommodation expenses from Janssen and Pfizer. Ò. Reig reports consulting or advisory role for BMS, EISAI, and Ipsen; and travel and accommodation expenses from Ipsen and Pfizer. L. Gaba reports advisory and consulting fees from GlaxoSmithKline, AstraZeneca, Merk Sharp Dohme, and PharmaMar, honoraria from GlaxoSmithKline, AstraZeneca, Merk Sharp Dohme, and PharmaMar for educational events/materials and travel expenses from GlaxoSmithKline, AstraZeneca, Merk Sharp Dohme. A. Prat reports advisory and consulting fees from AstraZeneca, Roche, Pfizer, Novartis, Daiichi Sankyo, and Peptomyc, lecture fees from AstraZeneca, Roche, Novartis, and Daiichi Sankyo, institutional financial interests from AstraZeneca, Novartis, Roche, and Daiichi Sankyo; stockholder and employee of Reveal Genomics; patents filed PCT/EP2016/080056, PCT/EP2022/086493, PCT/EP2023/060810, EP23382703 and EP23383369. F. Schettini reports honoraria from Novartis, Gilead, Veracyte and Daiichy-Sankyo for educational events/materials, advisory fees from Pfizer and Veracyte, and travel expenses from Novartis, Gilead and Daiichy-Sankyo. The other authors report no conflict of interest. Ethics approval and consent to participate: The study protocol was approved by the Ethic Committee of the HCB (IRB n. HCB/2017/0371) and was conducted according to the Declaration of Helsinki, good clinical practice guidelines and in compliance with applicable national and local laws. All patients signed an informed consent before entering the study., (© 2025. The Author(s).)

PURPOSE EXONERATE (EXOsome and cell-free micro-RNAs of anti-EGFR ResistAnce) was an open-label, biomarker interventional study designed to develop, test, and validate a liquid biopsy predictive of progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) for first-line EGFR inhibitors in metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Patients with newly diagnosed RAS-WT, chemotherapy-naïve mCRC, both right- and left-sided, were enrolled in 2-nationwide trials to receive cetuximab or panitumumab along with chemotherapy. The primary endpoint was 12-month PFS, which was hierarchically tested in left- and right-sided mCRC to predict PFS, OS, and ORR. RESULTS Genome-wide small-RNA sequencing identified 12 cell-free and 14 exosomal candidates that were differentially expressed in both plasma and tumor tissue of good vs. poor responders (based on PFS <12 months). The 8 and 9 best-performing candidates, respectively, were used to generate the EXONERATE assay. In left-sided mCRC, 65% were EXONERATE-high, correlating with shorter mPFS (9.5 vs. 18.5 months, p<0.001). In the independent right-sided mCRC cohort, 80.8% were EXONERATE-high and experienced a similarly shorter mPFS (8.6 vs. 41.2 months, p=0.0004). In the right-sided group, EXONERATE predicted PFS≥12 months with 100% sensitivity. A linear relationship existed between EXONERATE values and response depth. Multivariate analysis revealed that EXONERATE predicts PFS and OS independently of tumor-sidedness. CONCLUSION The EXONERATE assay robustly predicted PFS and OS outcomes in patients with mCRC, both right- and left-sided, before they received either panitumumab or cetuximab. It stratified PFS, OS, and ORR better than a right vs. left approach.