Sphingolipids as central regulators of therapy resistance and immunity in lung cancer

Lung cancer remains the deadliest cancer worldwide, with most patients exhibiting poor responses to current therapies and rapidly developing treatment resistance. Cancer cells can acquire resistance by rewiring their metabolism. In particular, dysregulated lipid metabolism promotes therapy resistance in multiple cancer types, including lung cancer. In addition to their role in shaping cell membrane, sphingolipids have recently emerged as key mediators of intra- and extracellular communication, triggering oncogenic signaling pathways and affecting immune cell functions. Through the accumulation of specific intermediates, such as ceramide derivatives, dysregulated sphingolipid metabolism can directly influence cell fate, ultimately promoting therapy resistance and immune escape. Consequently, sphingolipids are now considered as major regulators of resistance to chemo-, radio-, and immune checkpoint inhibition therapy. In this review, we will give an overview of the mechanisms by which sphingolipids orchestrate drug resistance and tumor immunity in lung cancer. We will also discuss the potential of targeting sphingolipid metabolism as a promising therapeutic strategy in lung cancer.