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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.

The N6-methyladenosine (m6A) methylase WTAP has been identified as a proto-oncogene in multiple cancers, including hepatocellular carcinoma (HCC). Interestingly, although WTAP expression does not differ between normal liver and HCC tissues or across different stages of HCC, patients with higher WTAP expression exhibit significantly shorter median survival times (MSTs). Here, we found that WTAP was upregulated in tumor-infiltrating CD8+ T cells, which were more enriched in HCC patients compared to the controls. HCC patients also displayed higher PD1 levels and a greater proportion of exhausted CD8+ T cells (TCF+ PD1+). Moreover, WTAP promoted PD1 expression and suppressed the proliferation and immune activity of CD8+ T cells. In the co-culture system, WTAP-overexpressing CD8+ T cells enhanced the malignancy of HCC cells. Notably, WTAP silencing further augmented the boosting effect of PD1 silencing on CD8+ T cell immune activity and strengthened its inhibitory effect on HCC cell growth. As an m6A ¡°writer¡±, WTAP increased the m6A level of PD1 mRNA, thereby promoting YTHDF1-mediated translation of PD1. Finally, in the HuNSG xenograft tumor model, WTAP knockdown not only alleviated CD8+ T cell exhaustion and inhibited tumor progression but also synergistically enhanced the antitumor efficacy of anti-PD1 therapy. In conclusion, WTAP promoted CD8+ T cell exhaustion and HCC progression by facilitating the m6A modification and translation of PD1 mRNA.