Targeting Metabolic Adaptation of Colorectal Cancer with Vanadium-Doped Nanosystem to Enhance Chemotherapy and Immunotherapy.

The anti-tumor efficacy of current pharmacotherapy is severely hampered due to the adaptive evolution of tumors, urgently needing effective therapeutic strategies capable of breaking such adaptability. Metabolic reprogramming, as an adaptive survival mechanism, is closely related to therapy resistance of tumors. Colorectal cancer (CRC) cells exhibit a high energy dependency that is sustained by an adaptive metabolic conversion between glucose and glutamine, helping tumor cells to withstand nutrient-deficient microenvironments and various treatments. We discover that transition metal vanadium (V) effectively inhibits glucose metabolism in CRC and synergizes with glutaminase inhibitors (BPTES) to disrupt CRC's energy dependency. Thus, a dual energy metabolism suppression nanosystem (VSi-BP@HA) is engineered by loading BPTES into V-doped hollow mesoporous silica nanoparticles. This nanosystem effectively dampens CRC energy metabolism, eradicating 33% of tumors in mice. Strikingly, the cell biological and preclinical model datasets provide compelling evidence showing that VSi-BP@HA not only reverses CRC cells chemo-resistance but also drastically potentiates anti-PD1 immunotherapy. Therefore, this nanosystem provides not only a promising approach to suppress CRC, but also a potential adjunct tool for enhancing chemotherapy and immunotherapy.