Polyphyllin I enhances the anti-tumor efficacy of Palbociclib by reversing M2 macrophage polarization in lung cancer

Lung cancer is a significant hazard to human health, with limited treatment options. Although CDK4/6 inhibitors like Palbociclib (Palb) have shown clinical promise, their effectiveness is often compromised by resistance. Our findings indicate that the Palb may promote M2-like macrophage polarization, which can facilitate tumor progression through immunosuppression. This study investigates the effect of Polyphyllin I (PPI) in counteracting Palb-induced M2 macrophage polarization and explored its synergistic anti-tumor potential when combined with Palb. In vitro, a macrophage polarization model showed that Palb enhanced the expression of M2 macrophage markers, which could be reversed by PPI. LLC cells were cultured with macrophage-conditioned medium (CM) showed that the PPI and Palb combination-CM group exhibited decreased proliferation, migration, and invasion capabilities in LLC cells and inhibited epithelial-mesenchymal transition (EMT) compared to the Palb-CM group. Moreover, the combination of PPI and Palb also enhanced anti-tumor effect in vivo. Mechanistically, the JAK-STAT pathway was enriched, and key signaling proteins associated with macrophage polarization, including TWEAK, p-JAK1 and p-STAT1, were significantly upregulated in the PPI-treated group. PPI can reverse Palb-induced M2 polarization by activating the TWEAK/JAK1/STAT1 signaling pathway, which can enhance the anti-tumor efficacy of Palb. These findings support PPI as a potential adjunct to CDK4/6 inhibitors for lung cancer therapy.