Metabolic Intervention Liposome Boosted Lung Cancer Radio-Immunotherapy via Hypoxia Amelioration and PD-L1 Restraint

At present, radiotherapy (RT) still acquires limited success in clinical due to the lessened DNA damage under hypoxia and acquired immune tolerance owing to the amplified programmed death ligand-1 (PD-L1) expression. Incredibly, intracellular PD-L1 expression depression is proven to better sensitize RT by inhibiting DNA damage repair. However, the disability of the clinically used antibodies in disrupting the extracellular PD-L1function still limits the effectiveness of radio-immunotherapy. Therefore, better PD-L1 regulation strategies are still urgently needed to better sensitize radio-immunotherapy. Hence, for this purpose, TPP-LND is synthesized by linking mitochondrial-targeted triphenylphosphine cations (TPP+) to the antineoplastic agent lonidamine (LND), which significantly reduces the dose needed for LND to induce effective oxidative phosphorylation inhibition (2 vs 300 mu M). Then, TPP-LND is wrapped with liposomes to form TPP-LND@Lip nanoparticles. By doing this, TPP-LND@Lip nanoparticles can sensitize RT by reversing the hypoxic microenvironment of tumors to generate more DNA damage and reducing the expression of PD-L1 via enhancing the adenosine 5 '-monophosphate-activated protein kinase activation. As expected, these well-designed economical TPP-LND@Lip nanoparticles are more effective than conventional anti-PD-L1 antibodies to some extent.

Automated summary

Currently, the limited success of radiotherapy in clinical practice is attributed to reduced DNA damage under hypoxia and acquired immune tolerance due to increased expression of PD-L1. This study demonstrates that intracellular PD-L1 depression can sensitize radiotherapy by inhibiting DNA damage repair. However, the effectiveness of radio-immunotherapy is still limited by the inability of clinically used antibodies to disrupt extracellular PD-L1 function. Therefore, better PD-L1 regulation strategies are urgently needed. The synthesis of TPP-LND and its encapsulation in liposomes can sensitize radiotherapy by reversing the hypoxic tumor microenvironment and reducing PD-L1 expression.