Piperlongumine Inhibits Lung Cancer Growth by Inducing Endoplasmic Reticulum Stress Leading to Suppression of M2 Macrophage Polarization

Lung cancer is the leading cause of cancer-related deaths globally. Prolonged targeted therapy use can lead to drug resistance and target mismatches, necessitating more effective and safer treatment strategies. Recent research has focused on the tumor microenvironment, which includes immune and stromal cells that play roles in tumor proliferation, metastasis, and neovascularization. Tumor-associated macrophages (TAMs) are key immune cells in the tumor microenvironment, promoting tumor invasion, metastasis, and immune escape. Their infiltration density in lung cancer tissue is a poor prognostic factor. Piperlongumine (PL), extracted from Piper longum, possesses antitumor and anti-inflammatory properties, inducing apoptosis and inhibiting invasion and metastasis in lung cancer cells. This study aims to elucidate the correlation between endoplasmic reticulum stress (ERS) in lung cancer cells and M2-type TAM polarization and the role of PL in regulating lung cancer progression. The network pharmacologic analysis revealed that Piperlongumine inhibits lung cancer progression by inducing endoplasmic reticulum stress. In vivo experiments demonstrated that Piperlongumine significantly reduced tumor volume and decreased the proportion of M2-type macrophages. Within the co-culture system, lung cancer cells were shown to promote macrophage M2-type polarization and enhance cancer cell migration. Piperlongumine effectively inhibited these effects by inducing endoplasmic reticulum stress in cancer cells, thereby reducing M2 polarization and cell migration. The addition of endoplasmic reticulum stress inhibitor 4-PBA counteracted Piperlongumine's effects, further underscoring the crucial role of ERS in the treatment mechanism. Piperlongumine suppresses lung cancer growth by inducing endoplasmic reticulum stress, which inhibits macrophage M2-type polarization and reduces cell migration. These findings support Piperlongumine's potential as a therapeutic agent and offer a foundation for targeting endoplasmic reticulum stress to modulate TAM function in lung cancer treatment.