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BackgroundThe imbalance of immune checkpoint molecules leads to immune escape of tumor cells. It has been established that KRAS mutation plays a key role in regulating PD-L1 expression of lung adenocarcinoma. However, the specific mechanism by which KRAS mutation regulates PD-L1 expression still needs further been clarified.MethodsThe relationship of KRAS mutation and ZNF24, SLC7A5 and PD-L1 expression in human lung adenocarcinoma tissues and cell lines were analyzed using relative assays. The effects of KRAS mutation on CD8+ T cell-dependent anti-tumor immunity via the ZNF24/SLC7A5/PD-L1 axis were analyzed through in vitro and in vivo experiments. Additionally, we examined whether and how targeting ZNF24 inhibits KRAS mutation-induced PD-L1 expression and evaluated the effect of ZNF24 inhibition and PD-L1 blocking on CD8+ T cell-dependent anti-tumor immunity.ResultsOur results found that KRAS mutation increases the expression of PD-L1 through the ZNF24/SLC7A5 axis and simultaneously inhibits the activation of CD8+ T cells in lung adenocarcinoma. Importantly, we discovered that Daptomycin (DAPT) binds to ZNF24 and inactivates it, representing the first reported inhibitor of ZNF24. DAPT combined with Anti PD-L1 monoclonal antibody may enhance CD8+ T cell-dependent anti-tumor immunity in KRAS mutated lung adenocarcinoma.ConclusionOur study provides the first evidence that KRAS mutation promotes immune escape in lung adenocarcinoma through the ZNF24/SLC7A5/PD-L1 axis.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12885-025-14336-0.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality, with resistance to PD-1 immune checkpoint inhibitors presenting a significant clinical challenge. Although the protein tyrosine phosphatase SHP2 has been implicated in immune evasion, its precise role in NSCLC and contribution to anti-PD-1 resistance remain poorly understood. To address this, we conducted a CRISPR-based screen which identified SHP2 as a pivotal factor promoting tumor escape from CD8 + T cell-mediated killing. SHP2 expression in NSCLC tissues was analyzed through immunohistochemistry (IHC), qRT-PCR, and Western blotting. Functional assays, including CCK-8 and colony formation, were employed to assess SHP2¡¯s role in tumor proliferation under IFN-¦Ã stimulation. Co-culture experiments with CD8 + T cells evaluated the modulation of immune responses. Mechanistic investigations focusing on IFN-¦Ã/STAT1/IRF1 signaling and CCL5 secretion were analyzed using bulk RNA sequencing, Western blotting, qRT-PCR, ELISA, and proximity ligation assays. We found that SHP2 overexpression correlated with advanced disease and poor prognosis. Mechanistically, SHP2 suppressed IFN-¦Ã/STAT1/IRF1 signaling, reducing CCL5 secretion and impairing CD8 + T cell cytotoxicity. SHP2 knockdown restored immune responses and sensitized tumors to anti-PD-1 therapy. Additionally, pharmacological inhibition of SHP2 with JAB-3312 reversed this immunosuppressive phenotype in NSCLC cell lines and patient-derived organoids (PDOs). Furthermore, in a syngeneic mouse model, JAB-3312 acted synergistically with anti-PD-1 antibodies to suppress tumor growth, an effect driven by a potent T-cell-intrinsic mechanism. These findings establish SHP2 as a key mediator of immune evasion and PD-1 resistance in NSCLC, and targeting SHP2 offers a promising therapeutic strategy to overcome immune resistance and improve responses to checkpoint blockade therapy.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12964-025-02498-0.

Post-transcriptional modifications to RNA, which comprise the epitranscriptome, play important roles in RNA metabolism, gene regulation, and human disease, including viral pathogenesis. Modifications to the RNA viral genome and transcripts of human immunodeficiency virus 1 (HIV-1) have been reported and investigated in the context of virus and host biology. However, the diversity of experimental approaches used has made clear correlations across studies, as well as the significance of the HIV-1 epitranscriptome in biology and disease, difficult to assess. Therefore, we established a reference HIV-1 epitranscriptome. We sequenced the model NL4¨C3 HIV-1 genome from infected primary CD4+ T cells and the Jurkat cell line using the latest nanopore chemistry, optimized RNA preparation methods, and the most current and readily available base-calling algorithms. A highly reproducible sense and a preliminary antisense HIV-1 epitranscriptome were created, where N6-methyladenosine (m6A), 5-methylcytosine (m5C), pseudouridine (psi), inosine, and 2¡¯-O-methyl (Nm) modifications could be identified by rapid multiplexed base-calling. We observed that sequence and neighboring modification contexts induced modification miscalling, which could be corrected with synthetic HIV-1 RNA fragments. We validated m6A modification sites with STM2457, a small molecule inhibitor of methyltransferase-like 3 (METTL3). We find that modifications are quite stable under combination antiretroviral therapy (cART) treatment, in primary CD4+ T cells, and in HIV-1 virions. Sequencing samples from people living with HIV (PLWH) revealed conservation of m6A modifications. However, analysis of spliced transcript variants suggests transcript-dependent modification levels. Our approach and reference data offer a straightforward benchmark that can be adopted to help advance rigor, reproducibility, and uniformity across HIV-1 epitranscriptomics studies. They also provide a roadmap for the creation of reference epitranscriptomes for many other viruses or pathogens.