Work

PCSK9 drives acquired resistance to anti-PD-1 immunotherapy through cystine metabolic reprogramming in lung cancer

Year: 2026

Type: article

Abstract: BACKGROUND: Acquired resistance (AR) represents a major obstacle to immune checkpoint inhibitor (ICI) therapy in lung cancer. However, its underlying mechanisms and reversal strategies remain unclear. METHODS: In this study, we analyzed paired tumor specimens from patients with AR to anti-programmed cell death protein 1 (PD-1) therapy and used mouse AR models, together with transcriptomic and metabolomic analyses, to investigate resistance mechanisms in lung cancer. RESULTS: We identify proprotein convertase subtilisin/kexin type 9 (PCSK9) as a key mediator of AR to anti-PD-1 therapy that suppresses CD8(+) T-cell function by reprogramming cystine metabolism in the tumor microenvironment. Mechanistically, PCSK9 interacts with KEAP1 (kelch-like ECH-associated protein 1) and facilitates its lysosomal degradation, leading to upregulation of the cystine transporter SLC7A11 in tumor cells. Elevated SLC7A11 enhances cystine uptake by tumor cells, limiting its availability for CD8(+) T cells and impairing their effector function. Furthermore, we demonstrate that PCSK9 upregulation in resistant tumors is induced by interferon-γ via the JAK1/2–STAT1 signaling axis. Importantly, inhibition of PCSK9 alleviates tumor-driven cystine competition, restores CD8(+) T-cell function, and resensitizes resistant tumors to anti-PD-1 therapy. CONCLUSIONS: These findings uncover a tumor-intrinsic immunometabolic mechanism of AR, wherein PCSK9 drives cystine competition between tumor cells and CD8(+) T cells and highlight PCSK9 as a potential metabolic checkpoint for overcoming AR in immune checkpoint inhibitor therapy.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-015974