Abstract
BackgroundPhotothermal therapy (PTT) is a highly effective treatment for solid tumors and can induce long-term immune memory worked like an in situ vaccine. Nevertheless, PTT inevitably encounters photothermal resistance of tumor cells, which hinders therapeutic effect or even leads to tumor recurrence. Naïve CD8+ T cells are mainly metabolized by oxidative phosphorylation (OXPHOS), followed by aerobic glycolysis after activation. And the differentiate of effector CD8+ T cell (CD8+ Teff) into central memory CD8+ T cell (CD8+ TCM) depends on fatty acid oxidation (FAO) to meet their metabolic requirements, which is regulated by adenosine monophosphate activated protein kinase (AMPK). In addition, the tumor microenvironment (TME) is severely immunosuppressive, conferring additional protection against the host immune response mediated by PTT.MethodsMetformin (Met) down-regulates NADH/NADPH, promotes the FAO of CD8+ T cells by activating AMPK, increases the number of CD8+ TCM, which boosts the long-term immune memory of tumor-bearing mice treated with PTT. Here, a kind of PLGA microspheres co-encapsulated hollow gold nanoshells and Met (HAuNS-Met@MS) was constructed to inhibit the tumor progress. 2-Deoxyglucose (2DG), a glycolysis inhibitor for cancer starving therapy, can cause energy loss of tumor cells, reduce the heat stress response of tumor cell, and reverse its photothermal resistance. Moreover, 2DG prevents N-glycosylation of proteins that cause endoplasmic reticulum stress (ERS), further synergistically enhance PTT-induced tumor immunogenic cell death (ICD), and improve the effect of immunotherapy. So 2DG was also introduced and optimized here to solve the metabolic competition among tumor cells and immune cells in the TME.ResultsWe utilized mild PTT effect of HAuNS to propose an in situ vaccine strategy based on the tumor itself. By targeting the metabolism of TME with different administration strategy of 2DG and perdurable action of Met, the thermotolerance of tumor cells was reversed, more CD8+ TCMs were produced and more effective anti-tumor was presented in this study.ConclusionThe Step-by-Step starving-photothermal therapy could not only reverse the tumor thermotolerance, but also enhance the ICD and produce more CD8+ TCM during the treatment.Graphical
Highlights
Photothermal therapy (PTT), works by converting near-infrared (NIR) light energy into heat, attracted a lot of attention as a non-invasive and localized tumor treatment modality [1,2,3,4]
It was found that HAuNS-Met@MS presented a very low toxicity on 4T1 tumor cells, with over 80% cell viability after 48 h incubation even at 10 mg/mL, indicating that the preparation has good biosafety (Additional file 1: Figure S1A, B)
D CD8 + T cell viability after incubation with 2DG at different concentrations. (E) CD8+ T cell viability after incubation with Met at different concentrations for 24, 48 and 72 h. (F) Lactate release ratio of CD8+ T cells at different concentrations of 2DG. (G) Time–temperature curve of HAuNS at various concentrations. (H) Cell viability of B16F10 after various treatments. (I) Mitochondrial membrane potential of B16F10 was detected with JC-1. (J) Representative flow cytometry plots and quantification (K) of apoptosis rates of B16F10 cells. *p < 0.05, **p < 0.01
Summary
Photothermal therapy (PTT), works by converting near-infrared (NIR) light energy into heat, attracted a lot of attention as a non-invasive and localized tumor treatment modality [1,2,3,4]. Laser immunotherapy (LIT) in combined with local selective photothermal therapy is increasingly being developed in the treatment of metastatic tumors, since their interaction induces a long-term, systemic anti-tumor immunity via actively stimulating the immune system [11]. The NIR laser and the light-absorbing agent can induce an extremely increase of temperature in the target tissue, which result in a tissue destruction zone covering the target tumor mass selectively It causes tumor cells swell and break into pieces, releasing tumor antigens, such as tumor-associated antigens (TAA), thermally induced damage associated molecular patterns (DAMPs), and a large number of self-antigens, to activates dendritic cells (DCs). Photothermal therapy (PTT) is a highly effective treatment for solid tumors and can induce long-term immune memory worked like an in situ vaccine. The tumor microenvironment (TME) is severely immunosuppressive, conferring additional protection against the host immune response mediated by PTT
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
