The metabolic reprogramming of tumors, characterised by dysregulated glycolysis and mitochondrial dysfunction, drives profound tumor microenvironmental reworking that causes immune evasion and therapeutic resistance [1], [2], [3], [4]. The metabolic shift not solely depletes oxygen and vitamins but additionally generates extreme hypoxia, triggering the stabilization of hypoxia-inducible factor-1α (HIF-1α) [5], [6]. Accumulating proof has demonstrated that HIF-1α can drive the overexpression of CD73, a key ectoenzyme within the adenosinergic pathway, which catalyzes the conversion of extracellular ATP into immunosuppressive ADO [7], [8], [9], [10]. ADO suppresses antitumor immunity by binding to A2A receptors on cytotoxic T cells and pure killer (NK) cells, impairing their effector capabilities, whereas concurrently increasing regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), exacerbating the immunosuppressive tumor microenvironment [11], [12], [13], [14]. Paradoxically, typical therapies similar to radiotherapy (RT), whereas inducing DNA harm in most cancers cells, additionally upregulate CD73 expression by way of DNA damage-ATR-Chk1-STAT3 signaling, signaling in surviving tumor cells, creating an ADO-rich milieu that drives tumor metastasis and recurrence and limits therapeutic efficacy [15], [16], [17]. The impact of RT mediated upregulation of immunosuppressive CD73 expression highlights the important have to disrupt the CD73-adenosine axis to potentiate the efficacy of radioimmunotherapy.
In the meantime, the dysregulated metabolism of strong tumors additionally results in extracellular acidosis, characterised by lactate and proton accumulation [18], [19], [20]. Acidic pH (6.5–7.0) straight impairs the perform of immune cells, together with dendritic cell maturation and T cell receptor signaling, whereas selling the polarization of tumor-associated macrophages (TAMs) towards an immunosuppressive M2 phenotype [21], [22], [23], [24]. Moreover, acidosis stabilizes CD73 transcription by enhancing HIF-1α exercise, synergizing with hypoxia to amplify adenosine manufacturing [25], [26], [27]. Typical RT, although efficient in localized tumor management, inadvertently aggravates acidosis by rising glycolytic flux in radioresistant cells and disrupting vascular integrity, which additional restricts oxygen diffusion and exacerbates hypoxia [28], [29]. To this point, quite a few acid-neutralizing methods have been developed to mitigate extracellular acidosis [30], [31], together with small-molecule inhibitors concentrating on lactate transporters (e.g., monocarboxylate transporters, MCTs) [32], [33] and proton channel proteins (e.g., V-ATPase) [34], [35], [36]. Moreover, some nanoparticles able to the “proton sponge” impact, together with calcium carbonate (CaCO3) [37], [38], [39], [40] and manganese dioxide (MnO2) [41], [42] have been engineered to neutralize extra protons inside tumor areas and have proven promise in restoring radiosensitivity. Contemplating that the tumor microenvironment undergoes dynamic reworking, necessitates combinatorial modulation of metabolic reprogramming to attain sturdy therapeutic outcomes.
Layered double hydroxide (LDH) nanosheets, a category of anionic clay supplies, have emerged as a extremely promising nanoplatform as a consequence of their distinctive options together with versatile drug-loading capability, acid-responsive biodegradability, in addition to proton sponge impact [43], [44], [45]. On this work, we developed multifunctional Mn/Al layered double hydroxide nanosheets (LDH NSs) loaded with the CD73 inhibitor PSB-12379 (LDH@PSB) for simultaneous tumor acidosis neutralization and ADO blockade to boost radioimmunotherapy. LDH@PSB exhibited pH-responsive degradation, effectively releasing PSB-12379 and elevating tumor pH from ∼6.5 to ∼7.0. This alleviation of acidity enhanced radiation-induced apoptosis and immunogenic cell demise, rising extracellular ATP. Launched PSB-12379 suppressed radiation-induced CD73 upregulation, blocking ATP hydrolysis into immunosuppressive ADO. In the meantime, Mn2⁺ ions from LDH@PSB activated the cGAS-STING pathway, synergizing to alleviate tumor immunosuppression and amplify antitumor immunity. In B16F10 and CT26 tumor fashions, LDH@PSB mixed with radiotherapy considerably inhibited tumor progress and extended survival. Integration with anti-PD-1 remedy additional triggered systemic abscopal results, enhancing dendritic cell maturation, cytotoxic T cell infiltration, and reversing immunosuppression. This mix additionally induced sturdy antigen-specific immune response to inhibit distant tumor progress. Our technique successfully overcomes radioresistance by disrupting the acidosis-ADO axis and activating STING signaling, providing a promising method to potentiate radioimmunotherapy.
