Abstract C128: Disrupting the Oncobiosphere: CAF-Targeting Therapy with Penetrium™ Reverses Pseudo-Resistance in Tumors

Abstract Cancer-associated fibroblasts (CAFs), central regulators of the tumor microenvironment (TME), are increasingly recognized as key orchestrators of the oncobiosphere—an integrated and dynamic multicellular system that sustains tumor progression and therapy resistance. CAFs not only support cancer stemness and self-renewal but also actively contribute to the formation of pre-metastatic niches. The bidirectional crosstalk between CAFs and tumor cells promotes the accumulation of a desmoplastic and immunosuppressive extracellular matrix (ECM), which serves as a major physical and immunological barrier against chemotherapy, targeted therapy, and immunotherapy. Therefore, overcoming CAF-mediated pseudo-resistance by dismantling this pathological architecture represents a promising approach for improving cancer treatment efficacy. Penetrium™, a novel niclosamide-based therapeutic formulated using an organic–inorganic nanohybrid delivery system. In a patient-derived pancreatic cancer organoid (PCO)–CAF co-culture model, which recapitulates key features of the human oncobiosphere, Penetrium™ selectively eliminated CAFs without affecting normal fibroblasts. This CAF-directed modulation restored gemcitabine sensitivity under previously resistant conditions and achieved complete ablation of CAF-integrated organoids. These findings provide the first ex vivo evidence that targeting CAFs and remodeling the stromal niche can overcome stromal-driven pseudo-resistance and re-enable effective chemotherapeutic response. The ability of Penetrium™ was further validated in in vivo syngeneic models of aggressive tumors—including triple-negative breast cancer (TNBC), non–small cell lung cancer (NSCLC), and pancreatic cancer. In these models, combination treatment with anti–PD-1 immune checkpoint inhibitors significantly enhanced intratumoral infiltration of cytotoxic immune cells, transforming the oncobiosphere from an immune-excluded (“cold”) to an immunologically active (“hot”) state. This immune activation was accompanied by functional disruption of the stromal architecture and enhanced tumor penetration of co-administered anti–PD-1 antibodies, indicating that CAF depletion alleviated desmoplastic and immunosuppressive barriers to immunotherapy. Together, these results demonstrate the potential of Penetrium™ as a tumor microenvironment–modulating agent that selectively eliminates CAFs to dismantle and reprogram the oncobiosphere. By targeting the structural basis of tumor resistance, Penetrium™ offers a novel strategy to overcome pseudo-resistance and augment the efficacy of immune checkpoint inhibitors and other anticancer modalities across diverse tumor types. Citation Format: Sue Jang, Sunki Lim, EunByule Choi, Sujong Kim, Jason Kim, Aizhan Abdildinova, Hailey Choi, Jin-Ho Choy, Geun-woo Jin. Disrupting the Oncobiosphere: CAF-Targeting Therapy with Penetrium™ Reverses Pseudo-Resistance in Tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C128.