Thoracic malignancies, including lung adenocarcinoma and malignant pleural mesothelioma, remain associated with poor prognosis and limited durable responses in advanced stages. Although targeted therapies and immunotherapy have improved outcomes in selected patients, chemotherapy remains central for those without actionable mutations. Their treatment response is heterogeneous, presents limited benefit, and reliable predictive biomarkers of chemotherapy sensitivity are still lacking, representing a setting with a high clinical need and an opportunity for novel research strategies. These tumors frequently involve the pleural cavity and are commonly associated with malignant pleural effusion, contributing to respiratory symptoms and often requiring therapeutic drainage. Notably, malignant pleural effusion represents a clinically accessible source of viable tumor cells accessible through minimally invasive procedures. In this proof-of-concept study, we explored the feasibility of generating patient-derived organoids from malignant pleural effusion for functional drug testing in thoracic tumors. Organoids were established from five patients with advanced lung adenocarcinoma lacking targetable mutations and, as an illustrative case, from a patient with malignant pleural mesothelioma. The organoids recapitulated the tumor-specific phenotypic features as characterized by mutational profiling and immunohistochemistry, and were subjected to systematic chemotherapy drug screening with FDA-approved antitumor compounds to explore for alternative therapies. Candidate hits like Idarubicin, Tazemetostat or Vemurafenib were further examined through dose-response assays. These findings demonstrate the feasibility of generating patient-derived organoids from malignant pleural effusions and support their use as exploratory platforms for functional drug testing in thoracic malignancies. Further studies with larger cohorts and integrated molecular analyses are required to validate their potential clinical utility.