With the recent success of immune checkpoint blockade (ICB) in cancer immunotherapy, there has been renewed interest in evaluating the combination of ICB inhibitors with radiotherapy (RT) in clinical trials in view of the localized RT-initiated vaccination effect, which can be augmented further by systemic immune-stimulating agents. Unfortunately, traditional RT/ICB accompanies severe toxicity from high-dose ionizing irradiation and low response rate from RT-aggravated immunosuppression, among which M2-type tumor-associated macrophages (TAMs) play an important role. Herein, CpGdecorated gold (Au) nanoparticles (CpG@Au NPs) were fabricated to improve the RT/ICB efficacy by immune modulation under low-dose X-ray exposure, where Au NPs served as radioenhancers to minimize the radiotoxicity, and yet acted as nanocarriers to deliver CpG, a toll-like receptor 9 agonist, to re-educate immunosuppressive M2 TAMs to immunostimulatory M1 counterparts, thus arousing innate immunity and meanwhile priming T cell activation. When combined with an anti-programmed death 1 antibody, irradiated CpG@Au led to consistent abscopal responses that efficiently suppressed distant tumors in a bilateral GL261 tumor-bearing model. This work thus demonstrates that CpG@Au-mediated macrophage reeducation could efficiently modulate the tumor-immune microenvironment for synergistic RT/ICB.
Radiotherapy (RT) plays a central part in curing malignant tumors. However, the treatment outcome is often impeded by low radiation absorption coefficient and radiation resistance of tumors along with normal...
NSCLC treatment in view of that modeling suggests that nearly 80% of all the lung cancer patients have an evidence-based indication for RT during their cancer journey. [4] However, the overall survival rate in NSCLC patients with RT treatment is still far from satisfactory. A critical reason for RT failure is the presence of innate and therapyacquired radioresistant tumor cells. [5] Furthermore, RT could not precisely target tumors with curative doses, thereby causing irreversible damages to the adjacent healthy tissues and bringing serious side effects. [6] Therefore, it is urgent to develop new kinds of radiosensitizers to reverse radiation resistance yet improve tumor targeting.To sensitize tumor cells to ionizing irradiation and partially overcome their innate and/or adaptive RT resistance, various nanoparticles (NPs) containing high-Z elements, including gold (Au), hafnium (Hf), and bismuth (Bi), have been explored as possible radiosensitizers in consideration of their high X-ray photon capture crosssection and Compton scattering effect, which could enhance X-ray energy deposition within the tumor to achieve a high RT therapeutic index whilst at a relatively low X-ray dosage. [7][8][9][10] NPs with controllable morphology/size and readily surface modification attend to accumulate into tumor zones via enhanced permeation and retention (EPR) effect guided passive targeting, or ligand-receptor-mediated active targeting or a combination of both. [11][12][13] However, the therapeutic outcome of these
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