Quantitative profiling of intratumor immune heterogeneity identifies loss of immune diversity as a hallmark of cancer progression.

Immunological intratumor heterogeneity (ImTH) describes the variability in the types, spatial distribution, and functional states of immune cells within tumors. While evidence suggests that ImTH influences tumor progression and therapeutic response, few studies have provided a quantitative characterization of ImTH. Here, we present Scoring Immunological Intratumor Heterogeneity (ScImTH), a novel algorithm that quantifies ImTH by calculating the Shannon entropy of immune cell type proportions within the tumor microenvironment. Using bulk, single-cell, and spatial transcriptomic datasets, we show that reduced ScImTH scores are associated with unfavorable survival outcomes, tumor progression-related molecular and phenotypic features, immunosuppressive states, and resistance to immunotherapy across multiple cancer types. Compared with existing measures of tumor immunity, such as immune score and B-cell receptor diversity, the ScImTH score demonstrated stronger and more consistent associations with clinicopathological features. Notably, the ScImTH score outperformed established biomarkers, including tumor mutational burden and PD-L1 expression, in predicting immunotherapy response. These findings highlight the clinical potential of the ScImTH score as a biomarker for cancer prognosis and immunotherapy stratification. More broadly, our results support the hypothesis that loss of immune diversity is a hallmark of tumor progression.