Targeted disruption of Oncogenic Biosphere: A Paradigm Shift Beyond Cancer Cell-Centric Therapies

Abstract

Traditional cancer therapies have primarily focused on directly targeting malignant cells, yet this paradigm has consistently fallen short in addressing therapeutic resistance and metastasis1. These persistent challenges suggest that the tumors surrounding environment--not just the cancer cells themselves--plays a decisive role in treatment failure. In this study, we present an ecosystem-oriented strategy that targets the pathological microenvironment sustaining cancer progression. We repurposed niclosamide, an FDA-approved anthelmintic agent2,3, and enhanced its bioavailability by formulating Penetrium an orally deliverable nanotherapeutic composed of niclosamide, magnesium oxide, and hydroxypropyl methylcellulose. In syngeneic and xenograft models of triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC), Penetrium showed robust antitumor synergy when combined with standard therapies including anti-PD-1, paclitaxel, and anti-VEGF agents. Notably, Penetrium markedly blocked metastatic spread. Mechanistic analyses revealed that Penetrium remodels the tumor extracellular matrix (ECM), downregulates MMP-9, restores E-cadherin, and enhances immune infiltration-- thereby converting immune-excluded tumors into immune-permissive niches. Furthermore, in patient-derived pancreatic tumor organoids co-cultured with cancer-associated fibroblasts (CAFs), we demonstrated that tumor cell survival is critically dependent on the stromal context. Importantly, Penetrium selectively eliminated CAFs without affecting normal fibroblasts. These findings validate the oncogenic biosphere, and especially the CAF-rich stroma, as a critical therapeutic target. Our results underscore a shift from the conventional cancer cell-centric model to an oncogenic biosphere-disruption strategy that dismantles the structural and immunological defenses of desmoplastic cancers, offering a promising avenue for overcoming resistance and metastasis.