Dynamic therapy is an anti-tumor strategy based on reactive oxygen species (ROS), such as ·O2− and ·OH, to perform cytotoxicity on tumor cells. Due to tumor cells are more susceptible to ROS damage compared to normal cells, it has certain selective killing effect on tumor. Dynamic therapy typically involves the generation of ROS in the tumor microenvironment (TME) under exposure to specific external (e.g., light [1], ultrasound [2], or radio [3]) or endogenous (e.g., pH, enzymatic catalysis) stimuli through electron transfer on the oxidative components (such as O2 and H2O2) in circumstance [4,5]. This determines that dynamic therapy heavily relies on the oxidative state of the TME. However, the excessive proliferation of tumor cells and aberrant angiogenesis often lead to a hypoxic condition in most tumors, significantly reducing the generation of tumor-killing ROS, which becomes the critical factor causing the resistance of hypoxic tumors to dynamic therapy. Currently, most researches focus on exogenously enhancing oxygen concentration in hypoxic tumor tissues to improve the effectiveness of ROS-based anti-tumor performance [[6], [7], [8], [9]]. However, the inefficiency of O2 elevation strategies poses challenges in addressing the inadequate therapeutic outcomes. In our previous work, we employed an oxygen-independent electrodynamic therapy (EDT) where the H2O molecules and Cl− ions are absorbed onto the surface of platinum nanoparticles and undergo water dissociation in the presence of Cl− ions, producing high cytotoxic ROS [10,11]. Compared to other dynamic therapies, EDT exploits water in the TME to produce ROS rather than relying on oxygen, offering prominent advantages in the treatment of hypoxic tumors.

Due to its potent tumor-killing ability, EDT typically achieves the desirable tumor ablation effect in just a few minutes of treatment. However, the risk of tumor recurrence after treatment cessation remains a common challenge faced by many anti-tumor strategies [12,13]. Heterogeneous hypoxia, a common characteristic of the TME in various types of tumors [14], is capable of reducing tumoral immunogenicity and promoting tumor immune escape via altering the function or activity of hypoxia-inducible factor 1 alpha (HIF-1α) to regulate the homeostasis between oxygen and free radicals [15]. Specifically, under hypoxic conditions, elevated HIF-1α expression can exacerbate the excessive infiltration of myeloid-derived suppressor cells (MDSCs) [16], play a critical role in restricting antigen presentation, suppressing T cell function, and driving the polarization of tumor-associated macrophages (TAMs), thereby directly exacerbating immune tolerance and finally resulting in an immunosuppressive TME [17]. Therefore, although a single session of a few minutes' EDT can achieve complete ablation of solid tumors, and various dynamic therapies including EDT have been proved to strengthen tumor immunogenicity by eliciting temporary immunogenic cell death (ICD) effects, but fails to exert its effects in an immunosuppressive environment with high MDSCs infiltration. Recently, despite attempts by researchers to combine EDT with other treatment modalities such as starvation therapy [18], chemotherapy [19], and immunotherapy [20] to reduce the risk of tumor recurrence, strategies focusing on MDSCs modulation, such as inhibiting MDSCs maturation [21,22], depleting MDSCs [23,24], or intervening MDSCs differentiation to TAMs [25,26], are considered to have great potential in reversing the immune-suppressive TME and promoting the synergistic effects with other anti-tumor approaches. Addition to the immune response induced by EDT alone, the combination with MDSCs inhibitor offers an opportunity for potentiation through local or systemic immune mechanisms, which referred to as electro-immunotherapy.

Here, based on electro-immunotherapy and we constructed a systemic administration immunotherapy platform LPPI (LP@Pt-Pd@IPI549 nanoparticles) using ROS-responsive phospholipid to modify PtPd nanocrystals loaded with the MDSCs inhibitor IPI549 for O2-independent EDT and immune cascade therapy (Fig. 1). LPPI passively accumulated in tumor tissues through the enhanced permeability and retention (EPR) effect. A single dosage of 5 min-electrical stimulation efficiently induced the EDT effect and achieved complete eradication of solid tumor tissues. Simultaneously, the phospholipid outer layer of LPPI was oxidized in situ and triggered degradation in response to the ROS generated during the EDT process, allowing cascade release and precise drug delivery of IPI549 at the site exposed to electric field. On one hand, EDT itself induced ICD effect to promote tumor immunogenicity. On the other hand, the released IPI549 suppressed the infiltration and function of MDSCs through inhibiting gamma isoform of phosphoinositide 3-kinase (PI3Kγ) pathway, thus reversing the immune-suppressive TME. The electro-immunotherapy of these two mechanisms resulted in an anti-tumor immune response. Therefore, this single-session EDT-immune cascade therapy platform provided an effective solution for the treatment of hypoxic solid tumors and held great potential for improving clinical patient compliance.