Reprogramming the Tumor Oncobiosphere: Bioactive Nanohybrid Materials for Reversing Therapeutic Pseudo-Resistance.

Tumor resistance is increasingly recognized as a systems-level phenomenon emerging from the collective behavior of the tumor ecosystem rather than solely from cancer cell-intrinsic genetic alterations. Here, we define the oncobiosphere as a functionally integrated, multiscale system that extends beyond the tumor ecosystem by incorporating not only cellular and molecular interactions but also extracellular matrix (ECM)-driven biophysical constraints and transport dynamics that shape therapeutic accessibility. Within this environment, reciprocal biochemical and biomechanical interactions promote pro-survival signaling, immune exclusion, and physical barriers that restrict therapeutic access, giving rise to pseudoresistance despite the absence of classical resistance mutations. Key signaling axes including integrin-FAK, TGF-β, YAP/TAZ, STAT3, and Wnt/β-catenin converge to reinforce ECM remodeling, desmoplasia, and impaired drug penetration. These pathways stabilize a protective microenvironment through extrinsic feedback loops rather than intrinsic tumor adaptation. In this context, nanobiotechnology offers new opportunities to modulate stromal dynamics. Nanoengineered agents, such as nanoniclosamide (nano-NIC), and ECM-targeting delivery systems may disrupt pathological matrix remodeling and restore tissue permissiveness. By reprogramming the oncobiosphere, therapeutic resistance can be viewed as a reversible ecological state, opening avenues for more durable anticancer responses across treatment modalities.