Targeting Cystine Metabolism in the Lung Cancer Environment Enhances the Efficacy of Immune Checkpoint Inhibition

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has shown promising therapeutic effects in the treatment of lung cancer, the overall efficacy of PD-1/PD-L1 inhibitors is only 20%-30%. Thus, more effective combination therapies are needed. This study finds that cystine and cysteine levels in tumor tissues of lung cancer patients are significantly higher than adjacent non-tumor tissues. Cystine deficiency polarizes macrophages toward an M1 phenotype, secreting more TNF-α, CXCL9, and CXCL10. However, using a cystine-free diet marginally reduces the development of lung cancer in vivo. A cystine-free diet slightly reduces lung cancer progression in vivo. Further studies show that cystine deprivation or erastin-mediated transport inhibition increased PD-L1 expression in macrophages both in vitro and in vivo. Combining a cystine-free diet or IKE injection with PD-L1 antibody treatment significantly inhibited subcutaneous tumor growth in mice. Mechanistic studies indicat that cystine deficiency-induced GSH depletion activates NF-κB in macrophages by reducing its glutathionylation. This effect can be reversed by replenishing GSH or using an NF-κB inhibitor. At the same time, lung cancer patients with better responses to immunotherapy are found to have lower serum GSH levels. These findings suggest that targeting cystine metabolism combined with PD-L1 inhibition is a promising therapeutic strategy.