The Role of Organoid‐Based Drug Sensitivity Testing in Clinical Cancer Therapy

In recent years, cancer has become a significant global health burden, with rising incidence rates emphasizing the need for innovative therapeutic strategies. Among these, organoid models have emerged as transformative platforms, offering unprecedented insights into tumor biology, drug screening, and therapeutic responses. This editorial explores the evolving role of organoids in precision oncology, highlighting their potential to bridge the gap between preclinical research and personalized medicine. In recent years, the incidence of cancer has steadily increased. According to the latest estimates from the International Agency for Research on Cancer, approximately one in five men or women will develop cancer during their lifetimes. This rising trend has heightened the demand for effective cancer therapies. Traditionally, treatment options have relied on surgery, chemotherapy, and radiotherapy, but recent advancements have shifted the focus toward targeted therapies and immunotherapies. However, tumor heterogeneity poses significant challenges, leading to the emergence of precision medicine as a key area of cancer research. Organoids have emerged as a novel model in this context. Organoids are three-dimensional structures derived from tissue stem cells and cultured in the presence of various growth factors necessary for cell proliferation. Compared with conventional cell lines, organoids more accurately recapitulate the architecture and functionality of the originating tissue while preserving the genetic stability and chromosomal diversity of the parent sample. These properties render organoids a preferred model for high-throughput drug screening and development. Organoid models in cancer studies demonstrated consistency with in vivo xenograft models and patient responses. One study established more than 100 organoids from both primary and metastatic breast cancers, and their histopathology, hormone receptor status, and HER2 expression closely mirrored those of the original tumors. Genetic information was largely preserved through serial passages, and drug responses observed in vitro aligned with the clinical outcomes in the corresponding patients [1]. Additionally, a pancreatic cancer organoid library was used to catalog the mutation profiles and transcriptional subtypes of primary tumors. These organoids facilitated longitudinal assessments of chemotherapy sensitivity and concurrent metastasis evaluation, offering insights into improved therapeutic responses in both adjuvant and advanced disease settings [2]. Organoids have also been employed to identify and validate biomarker–drug combinations. For instance, testing EGFR, FGFR, and MEK inhibitors in lung cancer organoids revealed that the models retained the targeted therapy sensitivity of their source tumors, reflecting the genomic and biological features of the patient tumors [3]. In a real-word study involving 107 patients with locally advanced or metastatic lung cancer, organoids accurately predicted clinical responses to chemotherapy and targeted treatments [4]. Organoids also offer a platform for modeling the tumor immune microenvironment. Coculturing organoids with immune cells enables the recreation of the immune milieu, providing a more physiologically relevant model to study tumor behavior. There are two primary methods for establishing immune-enriched organoid cultures: retaining and expanding endogenous immune cells within the tumor organoids and introducing exogenous immune cells into the culture system, which facilitates the evaluation of immunotherapy responses [5]. The organoid–immune coculture model has proven effective for evaluating immune checkpoint inhibitors. For example, studies demonstrated that both human and murine-derived organoids could successfully simulate immune checkpoint blockade, with anti-PD-1 and anti-PD-L1 treatments inducing the expansion and activation of tumor antigen-specific tumor-infiltrating lymphocytes, thereby triggering tumor cell cytotoxicity [6]. Organoids also serve as valuable preclinical models for CAR-T cell therapy, and the simulation of the tumor microenvironment was enhanced by incorporating tumor-associated immune components. In coculture systems, organoids derived from healthy human tissues are introduced to evaluate the potential off-target toxicity of CAR-T cells on nontarget tissues. High-throughput technologies enable the systematic testing of various combinations of tumor organoids and CAR-T cells, facilitating the rapid assessment of CAR-T cell efficacy across multiple tumor types. One study developed a method for generating potent CAR-T cells from human-induced pluripotent stem cells by reprogramming naïve and memory T cells, followed by CAR engineering and integration with 3D organoid systems [7]. Organoids also assist in modeling and validating tumor evolution during drug screening. For example, bladder cancer organoid models revealed that drug responses are partially correlated with mutation profiles and resistance-associated shifts, which were further validated using in vivo xenograft models [8]. Organoids have proven valuable in predicting individual sensitivity to specific drugs and assessing the risk of drug-induced organ toxicity. A liver organoid-based toxicity screening study developed a hepatotoxicity prediction system capable of measuring cell viability, cholestasis, and mitochondrial toxicity across four concentrations of 238 commercially available drugs [9]. Lawrence and colleagues used human iPSC-generated kidney organoids to identify HMOX1 as a marker of oxidative stress-induced toxicity. Kidney organoids with two types of HMOX1 reporters were employed to detect nephrotoxic substances from a set of blinded compounds, highlighting the potential utility of kidney organoids as screening tools [10]. Despite their advantages as drug prediction models, organoids have certain limitations, such as a lack of cellular diversity and vascular systems. Ongoing research is focused on developing new culture conditions and technologies to address these challenges. However, with their high fidelity and scalability, organoids offer significant advantages in drug development and screening research. As technology evolves, organoids are poised to become an integral part of cancer therapy, bridging the gap between laboratory research and clinical application. Huan Yang, Yuhong Liu, and Leli Zeng: writing–original draft. Jia Li, Leli Zeng, Yulong He, and Yihang Pan: funding acquisition, conceptualization. Leli Zeng: writing–original draft, funding acquisition, conceptualization. The authors have nothing to report. The authors have nothing to report. The authors have nothing to report. Professor Yulong He, Yihang Pan, and Leli Zeng are members of the Organ Medicine Editorial Board. To minimize bias, they are excluded from all editorial decision-making related to the acceptance of this article for publication. The remaining authors declare no conflicts of interest. The authors have nothing to report.