Tumor-Immune Microenvironment of Early-Onset Colorectal Cancer: Implications for Immune-Based Prevention and Therapy.

Abstract

Early-onset colorectal cancer (EOCRC), typically defined as colorectal cancer diagnosed before 50 years of age, is increasing in incidence worldwide and exhibits distinctive clinical, molecular, and environmental features compared with later-onset (LOCRC) disease. However, the tumor-immune microenvironment (TiME) of EOCRC and its implications for prevention and therapy remain poorly characterized. In this review, we synthesize current evidence on the TiME of EOCRC and contrast it with that of conventional LOCRC. We first discuss global features of the EOCRC immune landscape, including innate and adaptive immune composition, functional states, and spatial organization, highlighting areas where apparent age-related differences reflect true biology versus confounding by tumor site, stage, or mismatch repair (MMR) status. We then examine immunogenomic and epigenomic determinants-such as MMR deficiency distribution, microbial mutational signatures, chromosomal instability, and age-conditioned methylation programs-that shape neoantigen landscapes, antigen presentation, and immune evasion in younger patients. Next, we review microbiome-driven immunomodulation, focusing on dysbiosis, genotoxic bacteria, and early-life and young-adult exposures as joint modifiers of mucosal immunity and tumor development. Finally, we explore how these insights inform immune-based prevention (risk stratification, screening, diet and microbiome interventions, and chemoprevention) and immunotherapy strategies, including checkpoint blockade and rational combinations in the predominant microsatellite-stable EOCRC population.