From waste to wealth: malignant ascites-derived organoids as a compass for precision therapy in advanced gastrointestinal cancers

Peritoneal metastasis represents one of the most devastating trajectories in the clinical course of gastrointestinal (GI) malignancies. Once considered a terminal event managed solely by best supportive care, the paradigm has shifted over the last decade towards more aggressive multimodal strategies, including cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), although the majority of patients with malignant ascites are not candidates for such aggressive approaches (1). However, the efficacy of systemic and intraperitoneal chemotherapy remains highly heterogeneous. For patients with malignant ascites—a hallmark of advanced peritoneal dissemination—prognosis is particularly dismal, with median survival often measured in months (2). The current standard of care frequently relies on empirically selected prescribing of guideline-based regimens, which subjects patients to significant toxicity without guaranteed benefit. In this context, the development of functional precision medicine tools that can predict individual therapeutic responses ex vivo is an urgent unmet clinical need.

Patient-derived organoids (PDOs) have emerged as a powerful preclinical model, retaining the histological and genomic characteristics of the primary tumor more faithfully than traditional two-dimensional (2D) cell lines (3). While biopsy-derived organoids are gaining traction, they require invasive procedures that may be challenging or risky in patients with disseminated disease. In a recent issue of the Journal of Gastrointestinal Oncology, Yu et al. present a compelling study that addresses this limitation by utilizing malignant ascites—often discarded as medical waste during palliative paracentesis—as a source for establishing “malignant ascites-derived organoids” (MADOs) (4). Their work provides valuable evidence supporting the feasibility and predictive accuracy of this “functional liquid biopsy” approach in advanced GI cancers.

Yu et al. successfully established MADOs in 24 of 32 collected samples (75% success rate), covering a spectrum of pathologies including gastric, colorectal, pancreatic, and appendiceal cancers. This success rate is commendable and comparable to, if not higher than, some reported rates for tissue-derived organoids, suggesting that ascites provides an abundant and viable source of tumor cells (5). This finding aligns with a recent systematic review by Seghers et al., which analyzed 11 studies encompassing 190 organoids derived from malignant effusions and reported an average success rate of 84% (ranging from 33% to 100%) (5). Such high establishment rates underscore that malignant effusions are a robust and reliable source for organoid generation, potentially surpassing the efficiency of biopsy-derived cultures in certain contexts.

The authors demonstrated that these organoids maintained high histological concordance with the primary tumors. Crucially, they compared the ex vivo drug sensitivity profiles of MADOs with the clinical outcomes of 14 patients who received standard chemotherapy {e.g., XELOX [XELoda (capecitabine) + OXaliplatin], S-1 + OXaliplatin (SOX)}. The study reported an encouraging accuracy of 78.57–85.71% in predicting clinical response, with a significant Kappa agreement, reinforcing the potential of MADOs to guide decision-making in this difficult-to-treat population. Although the clinical correlation analysis was limited to 14 patients, the observed concordance is noteworthy given the extreme heterogeneity and poor prognosis of this population.

One of the most pragmatic aspects of this study is the authors’ handling of the definition of “clinical response”. In the setting of end-stage metastatic disease, stable disease (SD) is often clinically meaningful, preventing symptom deterioration and prolonging survival. The authors performed a dual analysis, evaluating concordance when SD was classified as either a “good” or “poor” response. Interestingly, the concordance was robust in both scenarios, though the highest Kappa value of 0.714 (range, 0.571–0.714) was achieved when SD was grouped with partial response (PR) as a favorable outcome. This nuance is critical for clinicians, as it suggests that MADOs may be particularly effective at identifying patients who will derive some benefit (disease control) versus those who are completely refractory to a specific regimen.

MADOs should not be viewed as a replacement for clinical judgment, but rather as a complementary decision-support tool in the management of patients with malignant ascites. However, as we move from “promising models” to clinical implementation, several challenges highlighted by this study and the broader literature must be addressed. First, the turnaround time for organoid establishment and drug testing (approximately 2–3 weeks total) remains a bottleneck. For patients with rapidly progressing malignant ascites and deteriorating performance status, this window is narrow. While faster than patient-derived xenografts (PDX), further optimization to accelerate culture expansion and automated drug screening is necessary to make “real-time” precision medicine a reality.

Second, the issue of tumor heterogeneity requires careful consideration. While Yu et al. showed that MADOs recapitulate the primary tumor’s histology, malignant ascites fluid represents a dynamic and heterogeneous mixture of shedding cells. A key question remains: do the floating cells used to grow MADOs accurately reflect the biology of the solid peritoneal deposits that are often the target of systemic therapy? Discrepancies between the chemosensitivity of circulating tumor cells and solid metastases have been observed in other contexts. As noted by Seghers et al., while effusion-derived organoids generally retain the genomic landscape of the primary tumor, inconsistencies in drug response between organoids derived from liquid biopsies versus solid metastases in the same patient have been reported (5). Future studies comparing the drug response profiles of ascites-derived organoids versus synchronous tissue-derived organoids from peritoneal nodules in the same patient would be enlightening to elucidate the extent of inter-metastatic heterogeneity.

Third, the current MADO model, like most standard organoid cultures, consists primarily of epithelial tumor cells and lacks the complex tumor microenvironment (TME), including immune cells, fibroblasts, and vascular components. This limitation is acknowledged by the authors but is particularly relevant given the rising role of immunotherapy [e.g., programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors] in GI cancers, such as MSI-high colorectal or gastric cancer (6). The standard MADO model used in this study cannot predict response to immunotherapies that rely on T-cell interaction. As the authors rightly suggest, the next frontier involves co-culture systems that incorporate autologous immune cells from the ascites fluid—which is naturally rich in tumor-infiltrating lymphocytes—to evaluate immune-checkpoint inhibitors alongside cytotoxic agents.

Finally, the standardization of drug sensitivity assays is paramount. Yu et al. utilized cell viability assays (CellTiter-Glo) and defined sensitivity based on dose-response curve morphology and inhibition rates. While their definitions were internally consistent based on their database, the field lacks a universal consensus on what constitutes “sensitivity” in an organoid assay [e.g., half-maximal inhibitory concentration (IC₅₀) thresholds vs. area under the curve]. The lack of uniform terminology—distinguishing between short-term cultures and established organoid lines—and standardized success criteria poses a significant obstacle to the systematic interpretation of studies across institutions (5). For MADOs to be integrated into guidelines [National Comprehensive Cancer Network (NCCN) or otherwise], multi-institutional validation with standardized protocols and predefined cut-off values is essential.

In conclusion, the study by Yu et al. represents a significant step forward in the management of peritoneal surface malignancies. By transforming a palliative procedure (paracentesis) into a diagnostic opportunity, they offer a less invasive, cost-effective window into the tumor’s biology. While challenges regarding TME modeling and standardization remain, the high success rate and clinical concordance reported here justify the expansion of this approach into larger, prospective clinical trials. If validated, MADOs could become an indispensable compass, guiding clinicians away from ineffective therapies and towards personalized regimens for patients who have little time to waste.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0028/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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