Immune biomarker landscape and fusion partner-phenotype associations in thoracic and head-and-neck NUT carcinoma.

BACKGROUND

Thoracic and head and neck NUT carcinoma is a rare, highly aggressive NUTM1-rearranged malignancy with substantial diagnostic difficulty, marked phenotypic heterogeneity, and no established biomarker framework for immunotherapy stratification. Although fusion partners may contribute to clinicopathologic diversity, their relationship to phenotype and immune biomarkers remains insufficiently defined.

MATERIALS AND

METHODS

We performed an integrated literature-based analysis of thoracic and head and neck NUT carcinoma using English-language publications indexed in the Web of Science Core Collection from 1991 to 2025. Eligible studies were screened for clinicopathologic, fusion, and immune-biomarker data. Case-level variables were harmonized into anatomic and lineage-based strata to evaluate associations between fusion partners, phenotype, and immune features. PD-L1 status was harmonized into three descriptive categories based on author interpretation and/or reported TPS/CPS thresholds, and a binary sensitivity framework, Negative versus Any expression, was additionally applied to reduce the impact of heterogeneous assays and scoring systems. MSI and TMB were also extracted when available. Associations were assessed using two-sided Fisher's exact test with odds ratios and 95% confidence intervals. To strengthen the robustness and translational relevance of the findings, we additionally analyzed an independent retrospective institutional cohort of thoracic and head and neck NUT carcinoma.

RESULTS

The integrated clinicopathologic dataset included 229 thoracic/head and neck cases with definitive fusion annotations from 109 studies. Squamous lineage predominated (71.62%), but non-squamous and mixed phenotypes were also identified. BRD4::NUTM1 was significantly enriched in squamous lineage and thoracic squamous subsets, whereas YAP1::NUTM1 and MGA::NUTM1 were preferentially associated with non-squamous phenotypes and specific strata. In the immune-biomarker subset, PD-L1 was predominantly negative (76.92%), with high expression being uncommon (6.41%). Thoracic squamous tumors showed significant enrichment for PD-L1 negativity. Among cases with both fusion and PD-L1 data, a binary sensitivity analysis confirmed that PD-L1 negativity predominated across fusion-defined subsets, with no significant association between fusion partner and PD-L1 status. Across reported MSI/TMB cases, tumors were uniformly MSS and generally low in TMB. An independent institutional cohort of 59 patients partially corroborated the major literature-derived signals, particularly BRD4::NUTM1 predominance among fusion-annotated cases and PD-L1 negativity among tested tumors, with no significant difference from the literature-derived pooled estimates.

CONCLUSION

This study defines the immune biomarker landscape of thoracic and head and neck NUT carcinoma within a clinicopathologic and fusion-partner framework. The predominance of PD-L1 negativity together with MSS/low-TMB features suggests a generally immunologically "cold" phenotype in most reported tumors, while exploratory fusion partner-specific enrichment patterns may help refine diagnostic suspicion and generate hypotheses for future biomarker-guided stratification. These findings provide a translational basis for rare-cancer immunobiology research and for the rational design of biomarker-integrated prospective studies.