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Cancer Cells and Metastasis / Immune Cells in Cancer · Journal article
Journal for Immunotherapy of Cancer · August 1, 2026
Encouraging direction, but not yet definitive.
This preclinical study identifies NCCRP1 as a regulator of tumor immune evasion in lung adenocarcinoma and shows that its deletion restores anti-tumor immunity in immunocompetent mouse models through a mechanistic pathway involving CX3CL1 upregulation and enhanced T-cell and macrophage infiltration. NCCRP1 loss also synergizes with anti-PD-1 and interferon-γ therapy to achieve complete tumor eradication in mice, supporting NCCRP1 as a candidate therapeutic target that warrants further investigation in human disease.
Preclinical mechanistic study with in vivo mouse tumor models. Mouse lung adenocarcinoma cell lines (subcutaneously transplanted); analysis motivated by publicly accessible patient-derived single-cell RNA sequencing and bulk RNA sequencing data. Intervention: CRISPR-Cas9 knockout of Nccrp1 gene in mouse lung adenocarcinoma cells; in vivo combinations with anti-PD-1 or interferon-γ therapy. Compared with: Wild-type (control) tumor cells; standard monotherapies (anti-PD-1 or interferon-γ alone, implied).
Loss of NCCRP1 inhibits lung tumor growth and prolongs survival in immunocompetent C57BL/6 mouse models NCCRP1 deficiency upregulates CX3CL1, recruiting CX3CR1+ antitumoral macrophages that secrete CXCL9 and CXCL10 Upregulation of CXCL9 and CXCL10 enhances infiltration of CD8+ T cells and NK cells into the tumor microenvironment
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These findings suggest NCCRP1 targeting as a potential therapeutic strategy to overcome the cold tumor phenotype in human lung adenocarcinoma, but clinical efficacy remains untested. The synergy with anti-PD-1 is particularly relevant given widespread use of checkpoint inhibitors, but confirmatory studies in human samples and eventual clinical trials are necessary before therapeutic application.
Preclinical mechanistic study in mouse models demonstrating that NCCRP1 loss enhances anti-tumor immunity and synergizes with checkpoint inhibition, but findings require translation to human clinical trials.
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Quoted from the source exactly as published.
These findings suggest NCCRP1 targeting as a potential therapeutic strategy to overcome the cold tumor phenotype in human lung adenocarcinoma, but clinical efficacy remains untested. The synergy with anti-PD-1 is particularly relevant given widespread use of checkpoint inhibitors, but confirmatory studies in human samples and eventual clinical trials are necessary before therapeutic application.
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Background The low response rate to immunotherapy in patients with lung adenocarcinoma is primarily due to tumor immune evasion. The tumor immunosuppressive microenvironment orchestrates this evasion, yet the underlying mechanisms remain elusive. Here we identify non-specific cytotoxic cell receptor protein 1 (NCCRP1) as a critical and previously uncharacterized regulator of this process. Methods We first analyzed publicly accessible patient-derived single-cell RNA sequencing and RNA sequencing data to investigate the expression of NCCRP1 in lung adenocarcinoma and its impact on the tumor immune microenvironment. Subsequently, the Nccrp1 gene was knocked out in mouse lung adenocarcinoma cells using CRISPR-Cas9. The effect of NCCRP1 deletion on tumor growth was then evaluated using subcutaneous transplantation models in both NSG and C57BL/6 mice. Single-cell RNA sequencing, flow cytometry and multiple targeted in vivo interventions were employed to assess the influence of NCCRP1 on the tumor immune microenvironment. To explore the underlying mechanisms by which NCCRP1 regulates the tumor immune microenvironment, we conducted co-immunoprecipitation, RNA pull-down, ubiquitination assay, mass spectrometry, isobaric tags for relative and absolute quantitation proteomics, dual-luciferase reporter gene assay, and ELISA. Results Loss of NCCRP1 inhibits lung tumor growth and prolongs survival in immunocompetent C57BL/6 mouse models. NCCRP1 deficiency upregulates CX3CL1 to recruit CX3CR1 + antitumoral macrophages. These macrophages subsequently secrete CXCL9 and CXCL10, enhancing the infiltration of CD8 + T cells and NK cells into the tumor microenvironment. Mechanistically, NCCRP1 and STAU1 competitively bind to NEDD4. NCCRP1 deficiency enhances the STAU1-NEDD4 interaction, promoting ubiquitination and proteasomal degradation of STAU1, thereby increasing CX3CL1 messenger RNA stability. Remarkably, ablating NCCRP1 synergized with anti-programmed cell death protein 1 or interferon-γ therapy, leading to complete tumor eradication. Conclusion Our findings highlight NCCRP1 targeting as a promising therapeutic strategy to reprogram the immunosuppressive microenvironment and overcome the “cold tumor” phenotype in lung adenocarcinoma.
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