Organoid-Based Transcriptomics Indicate IFIT-Associated Immune Modulation during Cryptotanshinone Treatment in Bladder Cancer

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Abstract Bladder cancer (BC), particularly muscle-invasive and metastatic disease, remains a major clinical challenge despite recent advances in immunotherapy. In this study, we aimed to identify a promising antitumor compound from five candidate small molecules and to explore its potential roles in BC progression. Through antiproliferative screening, cryptotanshinone (CTS) was identified as the promising candidate. Using both two-dimensional BC cell lines and three-dimensional bladder tumor organoid models, we comprehensively evaluated the effects of CTS on cell proliferation, migration, apoptosis, and organoid growth. To further explore the underlying mechanisms, transcriptomic sequencing based on bladder cancer organoid models, protein-protein interaction network analysis, and public databases (TCGA-BLCA, TIMER, and TISIDB) were integrated to examine immune-related pathways and potential molecular targets associated with CTS. GeneMANIA network prediction and molecular docking analyses were subsequently performed to investigate upstream regulatory networks and the potential interactions between CTS and key components of the cGAS-STING-IFN-I-JAK-STAT signaling pathway. Integrative analyses suggested that IFIT1, IFIT2, and IFIT3 may function as immune-associated genes potentially linked to BC progression, patient prognosis, immune cell infiltration, and PD-1/PD-L1 expression. Molecular docking results suggested that CTS may interact with core regulatory proteins within the cGAS-STING-IFN-I-JAK-STAT pathway, potentially influencing IFIT transcriptional regulation. Collectively, these findings indicate that CTS exhibits measurable antitumor and immunomodulatory effects, which may be associated with modulation of the cGAS-STING-IFN-I-JAK-STAT-IFIT signaling axis, supporting its potential as a small-molecule candidate for bladder cancer.

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