The oncogene c-MYC: an orchestrator of the tumor microenvironment and drug sensitivity in small cell lung cancer

Small-cell lung cancer (SCLC) is widely recognized as a notoriously refractory tumor, characterized by rapid proliferation, high aggressiveness, and early metastasis. Although immunotherapy combined with chemotherapy has become the standard of care for patients with extensive-stage SCLC, significant unmet needs, especially referring to lack of targeted therapy, persist in the clinic. The c-MYC proto-oncogene, one of the critical oncogenes, has been shown to be heavily associated with malignant tumor growth and drug resistance. c-MYC is amplified in SCLC and is further implicated in SCLC phenotypic plasticity, immune microenvironment composition, metabolic reprogramming, and therapy vulnerability, thereby playing the most key role in SCLC recurrence and devastating survival outcomes. This review summarized current knowledge on the mechanisms by which c-MYC regulates the SCLC oncogenic network and the status of drug development efforts targeted c-MYC . We also explore in detail that targeting c-Myc protein directly or indirectly represents a promising strategy for novel SCLC therapies. • High expression of c-MYC was related to SCLC development. • c-MYC drives SCLC subtype evolution and phenotypic plasticity. • c-MYC contributes to tumor microenvironment remodeling and immune evasion in SCLC. • Clinical trials on therapeutic strategies targeting c-Myc are underway.