Estrogen, estrogen receptor and the tumor microenvironment of NSCLC

Abstract Lung cancer remains the foremost cause of cancer‐related mortality worldwide. Clinical observations reveal a notable increase in both the proportion and mortality rate among female non‐small cell lung cancer (NSCLC) patients compared to males, a trend that continues to escalate. Extensive preclinical research underscores the pivotal role of estrogen in the initiation, progression, prognosis, and treatment response of NSCLC. Estrogen receptors are widely expressed in stromal and immune cells, influencing cellular activities across innate and adaptive immune systems. Immune evasion mechanisms significantly impact tumor development and outcomes, with immunotherapy offering promise in NSCLC by targeting these mechanisms. The intriguing gender disparities in immunotherapy responses prompt an exploration into the data on NSCLC occurrence, progression, and gender‐specific immunotherapy. Evidence highlights estrogen's contribution to a tumor‐permissive microenvironment, influencing various cells including cancer‐associated fibroblasts, macrophages, neutrophils, dendritic cells, natural killer cells, B cells, and T cells. Gender‐specific variations in NSCLC occurrence, development, prognosis, and treatment efficacy likely stem from interactions between estrogen, lung cancer cells, and these estrogen‐responsive cells, shaping a microenvironment conducive to tumor progression. Clarifying estrogen's role and its signaling pathways in NSCLC may unveil novel therapeutic strategies to modify the tumor microenvironment or enhance immunotherapy efficacy.