Beyond tumor mutational burden: a framework for immune-checkpoint blockade responsiveness in gastrointestinal cancers.

Immune-checkpoint blockade (ICB) elicits profound and durable responses in mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) gastrointestinal (GI) cancers, yet most microsatellite-stable (MSS) cancers derive minimal benefit. This gap reflects the limited ability of tumor mutational burden (TMB)-a widely used ICB biomarker-to capture true tumor immunogenicity. Only a small fraction of somatic mutations generates peptides that are processed, presented on HLA molecules, and recognized by T cells, and this pool is further restricted by defects in antigen-presentation pathways, including interferon unresponsiveness, epigenetic repression, and irreversible loss of B2M or HLA class I. These limitations have shifted attention toward neoantigen quality, defined by the presentability, clonal expression, and structural distinctiveness of mutation-derived peptides. Yet even high-quality neoantigens remain functionally irrelevant when presentation is impaired. To integrate these layers, we propose effective immunogenic burden (EIB) as a conceptual framework that describes the state in which tumor mutations generate high-quality neoantigen peptides that are successfully presented on HLA molecules for T-cell recognition. By integrating neoantigen quality and antigen-presentation capacity beyond TMB, EIB provides a clinically interpretable basis for understanding heterogeneous responses to ICB in GI cancers.