Targeting SERPINE1 enhances PD-1 blockade response by modulating macrophage infiltration and polarization through the STAT3-CCL2 axis in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer cases and drives one of the leading causes of cancer mortality worldwide. Immune checkpoint blockade targeting PD-1/PD-L1 has improved patient outcomes, but sustained tumor control is still limited. Tumor-associated macrophages (TAMs), the dominant myeloid population in the tumor microenvironment (TME), contribute to immune escape and immunotherapy resistance. Here, we identified tumor-intrinsic SERPINE1 as a critical driver of macrophage remodeling. SERPINE1 expression was strongly elevated in tissue microarrays, paired patient samples, and NSCLC cell lines. SERPINE1 knockdown limited tumor growth in immunocompetent mice, while growth differences were markedly reduced in immunodeficient mice, supporting immune involvement. Macrophage depletion attenuated the antitumor phenotype, indicating a macrophage-dependent mechanism. SERPINE1 silencing reduced TAM recruitment, decreased M2-like TAMs, and increased M1-like TAMs. Mechanistically, SERPINE1 inhibition reduced STAT3 phosphorylation and CCL2 production, a crucial chemokine involved in macrophage chemotaxis and polarization. Finally, in vivo experiments revealed that genetic targeting of SERPINE1 enhanced the efficacy of anti-PD-1 treatment, reduced tumor progression, and prolonged the survival of tumor-bearing mice. In conclusion, SERPINE1 inhibition restricts macrophage infiltration and shifts macrophage polarization away from M2-like phenotypes, enabling stronger tumor control when combined with anti-PD-1 therapy. These findings suggest the potential of targeting SERPINE1 as a strategy to enhance the efficacy of immunotherapy in NSCLC.