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In the CheckMate 142 study, nivolumab (anti-PD-1) alone and in combination with ipilimumab (anti-CTLA-4) was shown to induce durable clinical benefit in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer. Here, the authors perform exploratory biomarker analysis of the CheckMate 142 study.

Neoadjuvant immunotherapy can induce promising response rates in patients with localised deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) solid tumours but whether this translates to long term survival benefits is less clear. Here, the authors report long-term survival outcomes and ctDNA analysis of a phase II trial investigating neoadjuvant pembrolizumab in patients with dMMR/MSI-H solid tumours.

Treekitkarnmongkol, Katayama, Sankaran et al. identify RASH3D19 as a downstream target for KRAS signalling through miR-301a, which in turn leads to RAS activation and tumorigenesis. Targeting RASH3D19 inhibits growth of KRAS-mutant tumour cells in vivo.

Sebolt-Leopold and colleagues design and develop a small-molecule inhibitor that can target both epidermal growth factor receptor and phosphatidylinositol 3-OH kinase, which can be leveraged to overcome resistance to targeted therapies in vivo.

On the basis of encouraging preclinical activity, an anti-CEACAM5 antibody–drug conjugate with a topoisomerase 1 inhibitor payload is being tested in an ongoing phase 1 trial where recommended doses for further testing have been identified and an unconfirmed overall response rate of 15% was observed in patients with metastatic colorectal cancer.

Prespecified exploratory genomic and transcriptomic profiling of tumor tissues and circulating tumor DNA from patients with BRAF-V600E-mutant metastatic colorectal cancer who participated in the phase 3 BEACON CRC trial identifies biomarkers of response and mechanisms of acquired resistance to treatment with the BRAF inhibitor encorafenib plus the anti-EGFR antibody cetuximab, with or without the MEK inhibitor binimetinib.

mRNA vaccines have proven safe and effective in preventing serious illness and death during the COVID-19 pandemic. In this Comment, Morris and Kopetz argue that these technologies offer a novel approach towards personalizing immune-based treatments for patients with cancer with the potential for immune activation beyond commonly utilized immunotherapies.

As presented at the 2025 ASCO GI Cancers Symposium: in the phase 3 BREAKWATER trial, patients with previously untreated BRAF V600E metastatic colorectal cancer received the BRAF inhibitor encorafenib, the anti-EGFR monoclonal antibody cetuximab and chemotherapy mFOLFOX6 versus investigator’s choice of chemotherapy with or without bevacizumab, leading to an improved objective response rate, with the dual primary endpoint of progression free survival still maturing.

Feng, Luo and colleagues show that the combination of glucose and fructose, as found in sugar-sweetened beverages, promotes colorectal cancer metastasis through a mechanism involving sorbitol dehydrogenase (SORD).

A substudy of the CodeBreaK 101 trial, this phase 1b trial testing the KRAS-G12C inhibitor sotorasib with an anti-EGFR antibody shows an acceptable safety profile of this combination and encouraging preliminary clinical efficacy in patients with chemotherapy-refractory colorectal cancer.

Hofmann and colleagues describe the mechanism underlying the therapeutic benefit of combinatorial use of SOS1 and KRAS-G12C inhibitors in the context of KRAS-G12C mutant-driven lung and colorectal cancer.

The authors show that the lncRNA-derived microprotein SMIMP, which is shown to promote tumor formation, regulates cohesin core subunit binding to cis-regulatory elements and alters the expression of tumor-suppressive cell cycle regulators.

Cytotoxic T lymphocyte (CTL)-based immunotherapies can induce tumor regressions by targeting HLA class I-bound tumor-associated peptides. Here, the authors identified a peptide derived from Vestigial-like 1 (VGLL1) as a shared, potentially therapeutic CTL target expressed by multiple cancer types.

Total mRNA expression in cancer cells is a marker for disease progression and death.

Jung et al demonstrate that TMEM9 facilitates vacuolar-ATPase assembly to enhance vesicular acidification, thereby promoting activation of Wnt signalling and development of colorectal cancer.

Patient-derived xenograft models (PDX) have been extensively used to study the molecular and clinical features of cancers. Here the authors present a cohort of 536 PDX models from 25 cancers, as well as their genomic and evolutionary profiles and their suitability for clinical trials.

There is an urgent need to identify predictive markers for selecting responders to immunotherapy. Here, the authors describe a transcriptional predictor of immunotherapy response and assess it in genomic data from ~ 10,000 human tissues across 30 different cancer types.

An international consortium of colorectal cancer researchers undertakes a large-scale data sharing project to achieve a consensus molecular classification of colorectal cancers.

Analysis of copy number alterations in 1,451 patient-derived xenografts (PDXs) and matched patient tumor samples shows strong conservation from patient tumors through late-passage PDXs and a lack of systematic copy number evolution driven by the mouse host.

Analysis of a mass cytometry dataset for different human solid tumors coupled with murine reverse translational experiments suggests that targeting CD73 could enhance the efficacy of checkpoint inhibitor therapy in glioblastoma.

In 2018, advances were made in immunotherapy for colorectal cancers with microsatellite instability but, by contrast, immunotherapy studies in microsatellite-stable colorectal cancer had disappointing results. However, novel insights into the tumour microenvironment barriers that might limit therapeutic efficacy were identified, thereby offering new strategies.

In this Review, Dienstmannet al. analyse the complex nature of colorectal cancer and the different subtypes in which this disease can be classified, advocating for a 'multi-molecular' perspective for the development of therapies to treat it.

The analysis of ctDNA obtained from low-volume blood samples has the potential to transform the management of patients with colorectal cancer. Nevertheless, research priorities and minimum standards for sample collection and analysis in this area are currently missing. In this Position Paper, the NCI Colon and Rectal–Anal Task Forces provide a set of recommendations designed to address these challenges and accelerate the implementation of ctDNA in the management of patients with colorectal cancer.

Yazdani et al. identify gene signatures by integrating transcriptomic-causal networks into overall survival analysis, providing interpretable biomarkers for patient stratification. Gene signatures are found in metastatic colorectal cancer that indicate patients with specific profiles might benefit from cetuximab or bevacizumab.

With the development of novel targeted therapies for patients with colorectal cancer, comes a wealth of new, and increasingly complex information on biomarkers. In this Review, the authors describe this increased complexity, with a focus on interactions between more than one biomarker and the implications of these interactions for patient management.