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Background: Immunotherapy efficacy in esophageal squamous cell carcinoma (ESCC) is often limited by an immunosuppressive tumor microenvironment (TME). NLRC5, a key regulator of MHC-I antigen presentation, exhibits context-dependent roles in tumor immunity; however, its function in ESCC remains unclear. This study aimed to systematically investigate the expression pattern, prognostic value, and immunological role of NLRC5 in ESCC. Methods: An integrated analysis of bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) data was performed using multiple cohorts, including The Cancer Genome Atlas, Gene Expression Omnibus, and an in-house ESCC cohort. Differential expression, survival analysis, immune infiltration estimation, and functional enrichment analyses were conducted to elucidate the role of NLRC5 in the tumor microenvironment. Results: NLRC5 was significantly upregulated in ESCC and its high expression independently predicted poor patient survival. Although NLRC5 expression was associated with increased CD8+ T cell infiltration, it was paradoxically accompanied by features of T-cell exhaustion and elevated expression of multiple immune checkpoints. Moreover, NLRC5-high tumors were enriched in transcriptional programs related to PANoptosis, indicating an additional immunosuppressive mechanism within the TME. Conclusions: NLRC5 is not only a prognostic biomarker but also a key modulator of an immune-active yet functionally suppressed tumor microenvironment in ESCC. These findings highlight NLRC5 as a potential therapeutic target for restoring effective antitumor immunity.

Glioblastoma (GBM) is the most aggressive primary malignant brain tumor, and while chimeric antigen receptor-T (CAR-T) cell therapy has shown promise, its efficacy remains limited by antigen heterogeneity and immune escape. Here, we investigated the expression of B7 homolog 3 (B7-H3), epidermal growth factor receptor (EGFR), and interleukin-13 receptor alpha 2 (IL-13RA2) in GBM tissues and cell lines. Although all three antigens were highly expressed, sustained exposure to B7-H3 CAR-T cells led to significant B7-H3 downregulation but concurrent EGFR upregulation, revealing a potential immune escape mechanism. To address this heterogeneity, we engineered T cells to express an anti-B7-H3 CAR and secrete an EGFR-targeting bispecific T-cell engager (EGFR-BsTe). These B7-H3-CAR-T-EGFR-BsTe cells exerted dual functionality: direct B7-H3-dependent cytotoxicity and recruitment of unmodified T cells via secreted EGFR-BsTe to eliminate EGFR-expressing tumor cells. Notably, EGFR-BsTe secretion promoted CAR-T cell proliferation and effector differentiation. In orthotopic GBM xenograft models, including mixed tumors with heterogeneous antigen expression, B7-H3-CAR-T-EGFR-BsTe cells demonstrated superior antitumor activity and prolonged survival compared to conventional B7-H3 CAR-T cells. Quantitative analysis revealed that EGFR-BsTe secretion abrogated EGFR upregulation and enhanced B7-H3 downregulation in a target-dependent manner; however, efficacy was diminished when the CAR-Target (B7-H3) was absent on a substantial fraction of tumor cells. Our findings suggest that arming B7-H3 CAR-T cells with EGFR-targeting bispecific engagers represents a promising strategy to overcome antigen heterogeneity and improve therapeutic outcomes for GBM patients.

Autoantibodies against envelope (Env) protein encoded by human endogenous retrovirus group K (HERV-K) are prevalent in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), but it remains unclear which proviruses are responsible for this autoantigen. It also remains poorly understood how the transcription of HERV-K loci is regulated in cells that can produce Env.ResultsWe aligned our neutrophil RNA sequencing data to the new telomere-to-telomere reference genome and found uniquely mapping transcripts from HERV-K101, K102, K104, K108, K109, K117 and ERVK5, of which only K102, K108, and K109 encode an intact Env. Expression of K102 and K108 were higher in SLE than in healthy donors or RA (padj?<?0.05). Transcripts from these proviruses increased in response to interferon-¦Á in monocytes and neutrophils from RA patients and healthy donors, but not in SLE, presumably because they have chronically elevated type I interferons in vivo. Indeed, HERV-K expression was significantly higher in SLE patients with high type I interferon gene signature. Tumor necrosis factor-¦Á and other cytokines and TLR ligands also induced HERV-K102 and K108 transcripts. Interferon-¦Á also increased detectable Env protein in monocytes, macrophages, and neutrophils from RA patients. Among the genes for epigenetic silencers of HERV-K, only TRIM28 was significantly decreased in SLE patients with high interferons (padj?=?0.00024).ConclusionsOur data establish a role for interferons in maintaining increased HERV-K expression in SLE and suggest that interferons or other cytokines can upregulate HERV-K to similar levels in RA. A transient increase may also accompany normal immune responses, suggesting that endogenous retroviruses may have been co-opted for efficient immune responses.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13100-025-00371-y.