Mohapatra Adityanarayan, Mondal Jagannath, Sathiyamoorthy Padmanaban, Mohanty Ayeskanta, Revuri Vishnu, Rajendrakumar Santhosh Kalash, Lee Yong-Kyu, Park In-Kyu
Department of Biomedical Science, BK21 PLUS Center for Creative Biomedical Scientists, Chonnam National University Medical School, Gwangju 61469, South Korea.
Department of Green Bioengineering, Korea National University of Transportation, Chungju 27469, Republic of Korea.
ACS Appl Mater Interfaces. 2023 Mar 9. doi: 10.1021/acsami.3c01896.
Combined cancer immunotherapy has demonstrated promising potential with an amplified antitumor response and immunosuppressive tumor microenvironment (TME) modulation. However, one of the main issues that cause treatment failure is the poor diffusion and insufficient penetration of therapeutic and immunomodulatory agents in solid tumors. Herein, a cancer treatment approach that combines photothermal therapy (PTT) and nitric oxide (NO) gas therapy for tumor extracellular matrix (ECM) degradation, along with NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor that reduces tryptophan catabolism to kynurenine, and DMXAA, a stimulator of interferon gene (STING) agonist that stimulates antigen cross-presentation, is proposed to overcome this issue. Upon NIR (808 nm) laser irradiation, NO-GEL achieved the desired thermal ablation by releasing sufficient tumor antigens through immunogenic cell death (ICD). NO delivery triggered local diffusion of excess NO gas for effectively degrading tumor collagen in the ECM, homogeneously delivered NLG919 throughout the tumor tissue, inhibited IDO expression that was upregulated by PTT, and reduced the immune suppressive activities. The sustained release of DMXAA prolonged dendritic cell maturation and CD8 T cell activation against the tumor. In summary, NO-GEL therapeutics offer a significant tumor regression with PTT and STING agonist combination that stimulates a durable antitumor immune response. Additional unification of IDO inhibition during PTT supplements the immunotherapy by reducing the T cell apoptosis and immune suppressive cell infiltration to TME. NO-GEL with the STING agonist and IDO inhibitor is an effective therapeutic combination to counter possible limitations during solid tumor immunotherapy.
联合癌症免疫疗法已显示出有前景的潜力，具有增强的抗肿瘤反应和免疫抑制性肿瘤微环境（TME）调节作用。然而，导致治疗失败的主要问题之一是治疗和免疫调节药物在实体瘤中的扩散不良和渗透不足。在此，提出了一种癌症治疗方法，该方法将光热疗法（PTT）和一氧化氮（NO）气体疗法相结合以降解肿瘤细胞外基质（ECM），同时使用NLG919（一种吲哚胺2,3-双加氧酶（IDO）抑制剂，可减少色氨酸分解代谢为犬尿氨酸）和DMXAA（一种干扰素基因（STING）激动剂刺激剂，可刺激抗原交叉呈递）来克服这一问题。在近红外（808nm）激光照射下，NO-凝胶通过免疫原性细胞死亡（ICD）释放足够的肿瘤抗原，从而实现所需的热消融。NO的递送触发了过量NO气体的局部扩散，以有效降解ECM中的肿瘤胶原蛋白，在整个肿瘤组织中均匀递送NLG919，抑制PTT上调的IDO表达，并降低免疫抑制活性。DMXAA的持续释放延长了树突状细胞的成熟和针对肿瘤的CD8 T细胞活化。总之，NO-凝胶疗法通过PTT和STING激动剂组合提供了显著的肿瘤消退，刺激了持久的抗肿瘤免疫反应。在PTT期间额外联合IDO抑制可通过减少T细胞凋亡和免疫抑制细胞浸润到TME中来补充免疫疗法。具有STING激动剂和IDO抑制剂的NO-凝胶是一种有效的治疗组合，可应对实体瘤免疫疗法期间可能存在的局限性。
