Mapping intratumor heterogeneity across layers for advancing immunotherapy
Summary
Intratumor heterogeneity (ITH) encompasses genetic, epigenetic, transcriptional, proteomic, and immunopeptidomic diversity. Beyond genetic heterogeneity, it is increasingly clear that non-mutational heterogeneity and plasticity generate dynamic cancer cell states with distinct immune visibility. These layers of complexity converge on the immunopeptidome, the repertoire of peptides displayed by major histocompatibility complex molecules through which tumor cells are surveyed by T cells. Var
Content
# Mapping intratumor heterogeneity across layers for advancing immunotherapy
*Published: 2026 Apr 16*
Intratumor heterogeneity (ITH) encompasses genetic, epigenetic, transcriptional,
proteomic, and immunopeptidomic diversity. Beyond genetic heterogeneity, it is
increasingly clear that non-mutational heterogeneity and plasticity generate
dynamic cancer cell states with distinct immune visibility. These layers of
complexity converge on the immunopeptidome, the repertoire of peptides displayed
by major histocompatibility complex molecules through which tumor cells are
surveyed by T cells. Variation in antigen processing, presentation, and peptide
abundance across cancer clones and cell states yields spatially and temporally
distinct immunological niches that shape immune recognition and therapeutic
response. Here, we summarize how multidimensional ITH manifests across cancer
types and constrains immunotherapy efficacy. We propose that integrating
measurements across layers is a promising direction for improving biomarker
identification and informing more precise immune-based treatment strategies.
DOI: 10.1016/j.cell.2026.03.025