Intratumoral heterogeneity in small cell lung cancer and potential treatment strategies

Yunke Yang¹Nana Liu^2,3Jiaji Wu³Qingzhe Wu³Jiangnan Zhao³Yue Shi⁴Mo Shen³Zhiyong Xu³Yueli Shi³Jianghao Yu⁵Peng Yi⁶Jin Cheng⁷Junhui Sun⁸Yun Xu⁵Kai Wang^5*

• ¹Department of Mental Health, Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, China
• ²Department of Respiratory and Critical Care Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China, Yiwu City, Jinhua City, Zheji, China
• ³International Institutes of Medicine, Zhejiang University, Yiwu, China, Yiwu City, Jinhua City, Zheji, China
• ⁴The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
• ⁵The Fourth Affiliated Hospital Zhejiang University School of Medicine, Yiwu, China
• ⁶People's Hospital of Quzhou, Quzhou, China
• ⁷Wuxi Center for Disease Control and Prevention, Wuxi, China
• ⁸The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by early metastasis and poor prognosis due to the limited efficacy of current treatments. Although initially responsive to chemotherapy and radiotherapy, the majority of patients with SCLC develop resistance within a year, often succumbing to distant metastases. Historically, SCLC was considered a homogeneous disease, primarily driven by the deletion or inactivation of key tumor suppressor genes TP53 and RB1. However, recent advancements in genomics and single-cell sequencing have identified distinct molecular subtypes of SCLC, derived from studies on cell lines, animal models, and tumor tissues. The tumor's complexity, marked by the coexistence of multiple dynamic subtypes, contributes to its pronounced heterogeneity. Notably, different subpopulations exhibit a complex spatial relationship characterized by both mutual exclusion and coexistence. Temporally, SCLC exhibits the ability to undergo subtype transformations through various molecular mechanisms, underscoring the tumor's plasticity and offering novel perspectives for personalized treatment approaches. This review synthesizes recent discoveries regarding SCLC subtype classification, intratumor heterogeneity, plasticity-related signaling pathways, immune landscape, and emerging therapeutic strategies.