Targeting M2 Macrophages Enhances the Efficacy of PD-L1 Blockade in Non-small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) harboring KRAS G12D mutations and TP53 deficiency is associated with poor clinical outcomes, and effective therapeutic options remain limited. Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have made tremendous advances in lung cancer therapy over the last few years. Despite this, only a subset of patients receives durable clinical responses with PD-1/PD-L1 monotherapy. Tumor-associated macrophages (TAMs), especially M2 macrophages, play a critical role in shaping the immunosuppressive tumor microenvironment (TME) and in resistance to PD-L1 blockade. In this study, we utilized an interleukin-4 receptor (IL-4R)-binding peptide conjugated to the pro-apoptotic peptide (KLAKLAK)₂ (IL4RPep-1-KLA) to induce apoptosis in IL4R-expressing M2 macrophages. We found that both anti-PD-L1 antibody and IL4RPep-1-KLA monotherapy exhibited antitumor effect in NSCLC-bearing mice. Although co-administration of these two agents did not show a significant survival benefit, the combination markedly enhanced the infiltration of CD8 + T cells and granzyme B + cells within the tumor core, promoted systemic CD8⁺ T cell activation in the periphery and reduced the proportion of M2 macrophages in the TME. Thus, targeting M2 macrophages may provide a novel approach to remodel the immunosuppressive TME and potentially contribute to developing a new therapeutic modality that can address limitations of PD-L1-based therapies.