SHP2 inhibitors (SHP2i) alone and in various combinations are being tested in multiple tumors with overactivation of the RAS/ERK pathway. SHP2 plays critical roles in normal cell signaling; hence, SHP2is could influence the tumor microenvironment. We found that SHP2i treatment depleted alveolar and M2-like macrophages, induced tumor-intrinsic CCL5/CXCL10 secretion, and promoted B and T lymphocyte infiltration in Kras- and Egfr-mutant non–small cell lung cancer (NSCLC). However, treatment also increased intratumor granulocytic myeloid-derived suppressor cells (gMDSC) via tumor-intrinsic, NFκB-dependent production of CXCR2 ligands. Other RAS/ERK pathway inhibitors also induced CXCR2 ligands and gMDSC influx in mice, and CXCR2 ligands were induced in tumors from patients on KRAS^G12C inhibitor trials. Combined SHP2 (SHP099)/CXCR1/2 (SX682) inhibition depleted a specific cluster of S100a8/9^hi gMDSCs, generated Klrg1⁺ CD8⁺ effector T cells with a strong cytotoxic phenotype but expressing the checkpoint receptor NKG2A, and enhanced survival in Kras- and Egfr-mutant models. Our results argue for testing RAS/ERK pathway/CXCR1/2/NKG2A inhibitor combinations in patients with NSCLC.

Our study shows that inhibiting the SHP2/RAS/ERK pathway triggers NFκB-dependent upregulation of CXCR2 ligands and recruitment of S100A8^hi gMDSCs, which suppress T cells. Combining SHP2/CXCR2 inhibitors blocks gMDSC immigration, resulting in enhanced Th1 polarization, induced CD8⁺KLRG1⁺ effector T cells with high cytotoxic activity, and improved survival in multiple NSCLC models.

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