Targeting SHP2 to reverse immune evasion and resistance to anti-PD-1 therapy in non-small cell lung cancer.

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-γ stimulation. Co-culture experiments with CD8 + T cells evaluated the modulation of immune responses. Mechanistic investigations focusing on IFN-γ/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-γ/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.