Microsatellite-stable colorectal cancer, which accounts for roughly 80–85% of cases, remains largely refractory to immune checkpoint inhibitors compared with microsatellite instability-high tumors. This review synthesizes current evidence on tumor-intrinsic and microenvironmental mechanisms underlying immune checkpoint inhibitor resistance in microsatellite-stable colorectal cancer—including low neoantigen burden and impaired antigen presentation, activation of Wnt/β-catenin and MAPK signaling that exclude T cells, an immunosuppressive cellular milieu (regulatory T cells, myeloid-derived suppressor cells, M2-like tumor-associated macrophages, cancer-associated fibroblasts), metabolic reprogramming, and gut microbiome dysbiosis—and evaluates translational strategies aimed at overcoming these barriers. Preclinical and early-phase clinical data indicate that rational, mechanism-guided combinations (vascular normalization, myeloid reprogramming, metabolic inhibitors, antigen-priming approaches, and microbiome modulation) can enhance immune infiltration and produce benefits in biomarker-defined subgroups. Moving the field forward will require biomarker-driven, adaptive clinical trials with embedded translational endpoints to optimize patient selection and manage toxicity.

A randomized trial conducted by the Alliance for Clinical Trials in Oncology with support from the National Cancer Institute has found that duloxetine, a medication commonly used to treat chronic pain and psychiatric conditions, does not prevent nerve damage caused by chemotherapy in patients with colorectal cancer. The primary analysis of Alliance A221805 was published in JCO Oncology Advances.

Each year, about 85,000 adolescents and young adults (AYA) between the ages of 15 and 39 are diagnosed with cancer in the United States. According to the National Cancer Institute, this represents about 4% of all new cancer diagnoses.

Depending on age and specific diagnosis, many AYA people with cancer may be treated at either a pediatric cancer center or an adult cancer center. However, often these patients don’t feel comfortable in either setting as they feel too old for settings gear toward young children, but too young in centers where most of the patients are elderly.

This population also must navigate challenges surrounding normal milestones for others their age, such as pursuing an education, establishing a career or creating a family. Additionally, financial instability and lack of insurance coverage often deter AYAs from seeking timely medical attention, further complicating their prognosis.

The Alliance for Clinical Trials in Oncology and the Alliance Foundation Trials (AFT) have several active trials specifically poised to help the AYA population as well as others open to people in the AYA demographic.