From Cold to Constrained: Why MSS Colorectal Cancer Resists Immunotherapy

Abstract

Immune checkpoint blockade (ICB) has reshaped the treatment of multiple malignancies. However, its success in colorectal cancer (CRC) has been largely restricted to the minority of tumors exhibiting microsatellite instability-high (MSI-H) status. In contrast, microsatellite-stable (MSS) colorectal cancer remains largely refractory (1, 2). For nearly a decade, this resistance has been framed in deceptively simple terms: MSS tumors are “immune cold,” lack sufficient neoantigens, and therefore fail to respond to checkpoint inhibition. While conceptually convenient, this explanation has proven clinically insufficient. MSS CRC is not immunologically barren; rather, it is immunologically constrained. This commentary examines and contextualizes the accompanying review by Mi et al. on immune resistance in MSS colorectal cancer (3). Mi and colleagues present a timely and integrative reframing of MSS CRC immune failure, arguing that resistance to ICB is driven not by immune absence per se, but by a coordinated network of metabolic, microbial, and microenvironmental constraints that actively suppress immune competence. By integrating insights from tumor immunology, immunometabolism, and microbiome research, the authors propose a tripartite model in which host metabolism, gut dysbiosis, and immune suppression form a self-reinforcing ecosystem that limits the efficacy of checkpoint blockade alone. This reframing clarifies a long-standing misconception and directly informs therapeutic strategy. The persistence of the “cold tumor” paradigm may itself have delayed progress. By attributing failure primarily to the absence of immunogenicity, the field has often underprioritized reversible ecosystem-level barriers such as nutrient deprivation, stromal exclusion, and microbial conditioning. Reframing MSS CRC as constrained rather than inert, therefore, carries not only biological significance but therapeutic urgency.