Thymic epithelial tumors (TETs) are a diverse group of rare thymic tumors that arise from thymic epithelial cells. The rarity of these tumors has limited therapeutic advancements due to difficulty to enroll patients into Phase II and III clinical trials. Historically surgery, radiotherapy, and chemotherapy have been the mainstay therapeutic options for these patients with the development of new therapeutics hindered by the rarity, histological and molecular heterogeneity, and lack of actionable mutations. However, more recently, innovations in immunotherapy, next-generation tyrosine kinase inhibitors, and hyperthermic intrathoracic chemotherapy (HITHOC) have transformed the therapeutic landscape with more promising therapies currently under investigation. In this review we evaluate the histology and molecular subtypes of TETs, and discuss the therapeutic landscape including the current standard-of-care regimen as well as drugs that are currently in clinical trials.

Immune checkpoint inhibitors (ICIs) have transformed non-small cell lung cancer (NSCLC) treatment; however, durable responses occur in only a subset of patients, underscoring the need for robust predictive biomarkers. Serine/threonine kinase 11 (STK11) is an emerging biomarker that portends poor prognosis and predicts therapeutic resistance. Loss of STK11 disrupts AMPK signaling, leading to unchecked mTOR activation, metabolic reprogramming, angiogenesis, and epithelial–mesenchymal transition, fostering tumor progression and immune evasion. STK11 mutations frequently co-occur with KRAS and KEAP1 alterations, exhibit low PD-L1 expression, an immunosuppressive tumor microenvironment that leads to the development of PD-1/PD-L1 resistance. Clinical studies consistently demonstrate inferior outcomes with ICIs in STK11-mutant NSCLC, particularly in the presence of KRAS and KEAP1 co-mutations. Dual checkpoint inhibition combining PD-1/PD-L1 and CTLA-4 blockade shows promise in overcoming resistance, results remain inconsistent, and prospective trials are ongoing. Beyond immunotherapy, STK11 mutations confer poor outcomes across targeted therapies, including KRAS G12C inhibitors, with KEAP1 co-mutation serving as a strong negative predictor of efficacy. In this review we present an overview of STK11 function and its role in tumor biology, highlight the prognostic and predictive potential of STK11 mutations in the context of NSCLC treatment and summarize the emerging treatment strategies.