Tumor stays one of many main causes of morbidity and mortality worldwide, with roughly 14 million new circumstances and over 8 million deaths reported yearly[1]. Typical therapies similar to surgical procedure and chemotherapy usually fail to remove tumors utterly, resulting in decreased efficacy and elevated danger of recurrence and metastasis[2], [3], [4]. Lately, immunogenic cell loss of life (ICD) has emerged as a transformative strategy in tumor remedy, leveraging its skill to transform tumor cells into “immune vaccines” that elicit potent anti-tumor immune responses[5], [6]. This specialised type of cell loss of life is characterised by the discharge of damage-associated molecular patterns (DAMPs), which drives dendritic cells (DCs) maturation antigen presentation to cytotoxic T lymphocytes (CTLs), and subsequent activation of host immunity [7]. Regardless of its potential, the medical utility of ICD faces important hurdles. Its therapeutic success will depend on assembly three essential circumstances concurrently: (1) adequate technology of DAMPs is required to set off inflammatory cell infiltration and improve antigen presentation [8]; (2) the immune system have to be able to initiating a vigorous response and increasing inflammatory immune cells with tumor-killing potential [9]; and (3) The activated tumor-infiltrating inflammatory immune cells should be capable of survive and performance throughout the tumor microenvironment (TME), which is usually compromised by components similar to lactate accumulation pushed by the Warburg impact [10], [11]. This accumulation impairs the proliferation and effector features of inflammatory immune cells throughout the TME [11]. Addressing these challenges is essential for enhancing the therapeutic potential of ICD-based remedies for each main and distant tumors.
Endoplasmic reticulum (ER) stress performs a central position in coordinating the spatiotemporal dynamics of DAMP launch and their immunological recognition [12], [13]. It facilitates the floor publicity of calreticulin (CRT) and the nuclear launch of excessive mobility group box-1 protein (HMGB1), which synergistically drive inflammatory immune cell infiltration and provoke tumor-specific immune responses [7], [12]. Nevertheless, successfully inducing ER stress in tumor cells stays problem. Nanocatalyst-based therapeutic methods have emerged as a promising strategy to beat this limitation [14], [15]. These nanomaterials disrupt intracellular metabolic homeostasis and induce mitochondrial dysfunction, thereby triggering ER stress and activating the ICD pathway, which facilitates the growth of inflammatory immune cells with tumor-killing potential [7], [8], [9]. In the meantime, nanocatalyst-driven methods can regulate tumor cardio glycolysis, thereby decreasing lactate accumulation and enhancing the TME, thereby enhancing the infiltration and effector operate of inflammatory immune cells inside tumors [10], [16]. However, tumor cells, not like regular cells, exhibit important metabolic plasticity [17]. This enables them to activate compensatory pathways in response to ER stress, which compromises ICD induction and attenuates antitumor immune activation [18], [19], [20], [21]. As well as, tumor cells can maintain excessive lactate manufacturing even underneath glycolysis inhibition, as steady NAD+ (oxidized nicotinamide adenine dinucleotide) regeneration maintains redox homeostasis and fuels compensatory metabolic flux[10], [11], [22], [23]. This sustained NAD+ availability helps ongoing lactate technology, thereby aggravating immunosuppressive tumor microenvironments that hinder inflammatory immune cell survival and performance [22], [23]. Even when immune activation is efficiently initiated, the persistence of inflammatory immune cells is decreased, thereby limiting the therapeutic efficacy of nanocatalytic methods. Due to this fact, overcoming tumor metabolic adaptability and exactly regulating nanocatalytic reactions are essential for enhancing ICD induction and successfully reprogramming tumor metabolism, which stays a key barrier to the success of nanoparticle-based immunotherapy.
Amongst numerous nanoparticle sorts, transition metallic oxide-based nanocatalysts have emerged as extremely promising candidates as a result of their tunable properties, together with adjustable digital buildings, band gaps, and the exact management over composition and catalytic websites [14], [24]. These attributes make them invaluable for enhancing ICD induction and modulating tumor metabolism to beat metabolic adaptation [14]. Nevertheless, regardless of their substantial potential, these nanocatalysts face a big limitation: their catalytic effectivity is usually diminished by the robust chemisorption between catalytic websites and electronegative components, similar to oxygen [25], [26]. These interactions can result in the formation of thermodynamically steady, non-reactive floor complexes, which passivate lively websites and impede catalytic turnover [27], [28]. As well as, electron switch between adjoining lively facilities usually depends on bridging oxygen atoms, a pathway inherently restricted by the localized digital construction of oxygen, leading to poor conductivity and decreased catalytic dynamics [29], [30]. To beat these limitations, the introduction of oxygen vacancies (Ov) has emerged as a promising technique to control floor reactivity and optimize cost transport [31], [32]. By eradicating strongly sure oxygen atoms, these vacancies expose beforehand blocked lively websites, improve native electron density, and facilitate extra environment friendly cost switch by way of various pathways [31], [32], [33]. This enchancment in catalytic efficiency, mixed with the tunable digital properties of transition metallic oxides, is anticipated to synergistically improve their skill to induce immunogenic cell loss of life and disrupt tumor metabolic adaptation. Nevertheless, attaining exact spatial distribution and digital management of oxygen vacancies throughout synthesis, whereas preserving the structural defects and catalytic performance underneath physiological circumstances, stays a big problem.
On this work, we report a multifunctional immune nanocatalytic platform (denoted as G@Ir/MnFe-MMO) which, underneath 808 nm laser irradiation, synergistically disrupts tumor metabolic homeostasis, ICD, and successfully remodels the immune microenvironment, in the end attaining potent therapeutic results towards each main and distant tumors. As proven in Scheme 1, composite metallic oxides (MMO) wealthy in Ov, known as MnFe-MMO, have been first synthesized by topological transformation of MnFe-layered double hydroxide (LDH) nanosheet precursors. The Ov in MnFe-MMO acted as anchoring websites, facilitating the nucleation of high-valence Ir supported metallic clusters (Ir-SMCs) by way of a vacancy-induced mechanism. These Ir-SMCs possessed absolutely uncovered catalytic facilities and excessive oxidative potential, enabling environment friendly oxidation of decreased nicotinamide adenine dinucleotide (NADH). As well as, the Ov served as bridges for electron switch throughout the MnFe-MMO matrix, facilitating Mn to Fe electron switch by way of Mn−Ov−Fe pathways. This course of established favorable digital states, notably selling the formation of Fe2+ species which might be important for Fenton reactions, and thereby enhanced the environment friendly technology of reactive oxygen species (ROS). These structural options not solely facilitated the formation of ultrasmall Ir-SMCs but in addition enabled sustained electron switch, accelerated redox reactions, and considerably enhanced ROS catalytic exercise. To additional modulate tumor metabolism and enhance the immunotherapeutic end result, the lactate dehydrogenase A (LDHA) inhibitor GNE-140 (GNE) was loaded onto Ir/MnFe-MMO, yielding the ultimate multifunctional platform G@Ir/MnFe-MMO. Upon mobile uptake by 4T1 tumor cells, GNE inhibited LDHA exercise and disrupted cardio glycolysis. In the meantime, persistent NADH consumption and •OH manufacturing impaired the proton driving force and electron transport chain (ETC) in oxidative phosphorylation (OXPHOS), decreasing the cells’ metabolic flexibility. Importantly, LDHA inhibition concurrently prevents NAD+ regeneration from NADH, thereby synergizing with Ir-SMCs-mediated NADH depletion to break down the redox cycle. This twin interference breaks the compensatory NAD+-driven lactate manufacturing that sustains redox homeostasis underneath stress circumstances. This sustained interference triggered ER stress, in the end inducing apoptosis in 4T1 cells. Moreover, dying tumor cells launched DAMPs, confirming the induction of ICD. Concurrently, the interruption of tumor metabolism led to a big discount in extracellular lactate accumulation, reversing immunosuppression TME and selling infiltration of inflammatory immune cells inside TME. In abstract, we developed a potent multifunctional immuno-nanocatalytic platform that disrupts tumor redox steadiness and metabolic homeostasis. By reprogramming the immunosuppressive tumor microenvironment into an immune-active state and inducing sturdy ICD, this platform successfully initiated antitumor immune responses, enhanced immune cell infiltration, and in the end enabled secure and environment friendly tumor eradication.
