A novel nano-biocomposite synergistically activates PANoptosis and cGAS-STING for precise cancer immunotherapy.

Abstract

Although cancer immunotherapy has achieved significant progress in clinical practice, the uneven distribution of nanomaterials across the body, as well as the insufficient precision of current immunotherapy remain critical challenges. In this study, we proposed a novel strategy for precise cancer immunotherapy via synergistic activation of PANoptosis and innate immunity. Specifically, an innovative nano-biocomposite has been developed through the strategic integration of engineered Escherichia coli BL21 (EcBD) with biodegradable cerium-manganese hydroxide nanoparticles (CeMn(OH)_x NPs). Within the hypoxic tumor microenvironment, EcBD exhibited targeted aggregation and controllably released a membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (mTRAIL), which induced apoptosis through specific receptor recognition on tumor cells. Concurrently, the CeMn(OH)_x NPs underwent tumor microenvironment-responsive degradation, releasing Ce³⁺ and Mn²⁺ ions. Ce³⁺-mediated DNA damage and multi-organelle dysfunction led to inflammatory cascade activation to induce PANoptosis. Moreover, Mn²⁺ ions could bind to free DNA fragments to activate the cGAS-STING pathway. The coordinated PANoptosis and cGAS-STING-mediated immune activation could reverse tumor immunosuppression, effectively suppressing primary tumor progression and metastatic dissemination. This combined bacteria-nanomaterial approach for inducing PANoptosis and stimulating innate immunity offers a promising new direction for precision cancer immunotherapy.