Enhanced cGAS‐STING Activation and Immune Response by LPDAM Platform‐Based Lapachone–Chemical–Photothermal Synergistic Therapy for Colorectal Cancer

This study describes a multifunctional LPDAM nanotheranostic platform combining Lapachone, polydopamine, and Mn²⁺. It integrates Lapachone-mediated chemotherapy, polydopamine-induced photothermal therapy and immunogenic cell death, and Mn²⁺-driven chemodynamic therapy, synergizing to eliminate tumor cells while activating the cGAS-STING pathway for potent antitumor immunity.

Abstract

The cGAS-STING signaling pathway is a pivotal immune response mechanism that bridges tumor and immune cell interactions. This study describes a multifunctional LPDAM nanoplatform integrating Lapachone, polydopamine (PDA), and Mn²⁺, which synergistically kills tumor cells and activates the cGAS-STING pathway, thereby inducing DC maturation and T cell activation to achieve potent antitumor immunity. In the tumor microenvironment, Lapachone generates H₂O₂ via the NAD(P)H:quinone oxidoreductase 1 (NQO1 enzyme), while Mn²⁺ catalyze H₂O₂ conversion into •OH through chemodynamic effects (CDT). The photothermal effects (PTT) of PDA further amplify this cascade reaction, producing reactive oxygen species (ROS) that damage tumor mitochondria and release mitochondrial DNA (mtDNA). The released mtDNA activates the cGAS-STING pathway, while Mn²⁺ enhances the sensitivity of cGAS to mtDNA, leading to robust antitumor immunity. Concurrently, photothermal-induced immunogenic cell death (ICD) promotes dendritic cells (DCs) maturation, further strengthening immune responses. Moreover, Mn²⁺ also serves as a contrast agent for T1-weighted magnetic resonance imaging (MRI), offering precise tumor visualization. This study demonstrates that the LPDAM nanoplatform facilitates Lapachone/CDT/PTT synergistic therapy under MRI guidance, showcasing its potential as an innovative strategy for combined immunotherapy in clinical oncology.