Cyclic dinucleotides(CDNs)are natural agonists of the stimulator of interferon genes(STING),which is an attractive immunotherapy target.Currently,CDNs and their derivatives are being investigated clinically.However,th...Cyclic dinucleotides(CDNs)are natural agonists of the stimulator of interferon genes(STING),which is an attractive immunotherapy target.Currently,CDNs and their derivatives are being investigated clinically.However,the poor bioavailability of exogenous CDNs has limited their application in immunotherapy.Although nanocarriers are widely used for cytosolic delivery of CDNs,their loading capacity is insufficient,and their complicated composition and purification process raises bio-compatibility concerns.Herein,we report a super-simplified CDN self-assembly strategy for carrier-free delivery of CDNs.In the presence of excess K^(+),CDNs form oligomers which further self-assemble with divalent metal ions(such as Mn^(2+))to form nanoparticles(NPs)in aqueous solution.We demonstrate that the self-assembled CDN NPs promote cellular uptake of CDNs and enhance tumor immunogenicity by remodeling the tumor microenvironment,inducing immunogenic tumor cell death and increasing tumorinfiltrating lymphocytes,which is conducive to the generation of tumor neoantigen-specific T-cell responses.We also demonstrate that the use of CDN NPs alone or in combination with immune checkpoint blockades inhibits tumor growth,highlighting the fact that CDN NPs are a potent platform for cancer immunotherapy.展开更多
The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer treatment.Within this landscape,the innate immune system,a critical sentinel prote...The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer treatment.Within this landscape,the innate immune system,a critical sentinel protecting against tumor incursion,is a key player.The cyclic GMP-AMP synthase(c GAS)and stimulator of interferon genes(STING)pathway has been found to be a linchpin of innate immunity:activation of this signaling pathway orchestrates the production of type I interferon(IFN-α/β),thus fostering the maturation,differentiation,and mobilization of immune effectors in the tumor microenvironment.Furthermore,STING activation facilitates the release and presentation of tumor antigens,and therefore is an attractive target for cancer immunotherapy.Current strategies to activate the STING pathway,including use of pharmacological agonists,have made substantial advancements,particularly when combined with immune checkpoint inhibitors.These approaches have shown promise in preclinical and clinical settings,by enhancing patient survival rates.This review describes the evolving understanding of the c GAS-STING pathway's involvement in tumor biology and therapy.Moreover,this review explores classical and non-classical STING agonists,providing insights into their mechanisms of action and potential for optimizing immunotherapy strategies.Despite challenges and complexities,the c GAS-STING pathway,a promising avenue for enhancing cancer treatment efficacy,has the potential to revolutionize patient outcomes.展开更多
Cyclic dinucleotides(CDNs) are known to activate stimulator of interferon genes(STING) and induce type I interferon responses, therefor possess great potentials to be of immunotherapeutic value for cancers and infecti...Cyclic dinucleotides(CDNs) are known to activate stimulator of interferon genes(STING) and induce type I interferon responses, therefor possess great potentials to be of immunotherapeutic value for cancers and infectious diseases. However, the existence of different single nucleotide polymorphism(SNP) of human STING(hSTING) gene poses an obstacle to achieve broad-spectrum activation by CDNs. We reported here the design and synthesis of a total of 36 CDNs, representing all structural variations, that contain four bases(A, G, C, U) and two linkage directions(2′-5′-linked and 3′-5′-linked phosphodiester).Through systematic evaluation of IFN-β induction with a dual-luciferase reporter assay, we discovered that wild type hSTING and two isoforms(HAQ and AQ) showed strong response while hSTING-R232 H and R293 Q exhibited the relatively weak response to CDNs stimulation. For the first time, we found that the c[G(2′,5′)U(2′,5′)] showed excellent activity against all five hSTING variants even equivalent to the endogenous ligand c[G(2′,5′)A(3′,5′)]. Furthermore, we have also demonstrated that 3′-3′CDNs with two 3′-5′ phosphodiesters showed higher serum and hydrolase stability than 2′-2′ CDNs with two 2′-5′ phosphodiesters and 2′-3′ CDNs with one 2′-5′ and one 3′-5′ phosphodiester. It is very interesting to note that 2′-2′ CDNs has been found for the first time to show strong activity. These findings will stimulate our exploration for the new functional role of CDNs, and provide guidelines to design CDNs based hSTING targeted drugs.展开更多
An NAD analogue, N-(2-thiol-ethyl)-nicotinamide (TENA), was synthesized. TENA was used to modify the Au electrode through self-assembled monolayer.The cyclic voltammetry study of the electrode was carried out. The int...An NAD analogue, N-(2-thiol-ethyl)-nicotinamide (TENA), was synthesized. TENA was used to modify the Au electrode through self-assembled monolayer.The cyclic voltammetry study of the electrode was carried out. The interference of dimerization of the NAD analogues reported in the literature was successfully avoided. The results support a mechanism of an electron transfer followed by chemical reaction during part of the redox process of TENA. Some useful reaction parameters were obtained.展开更多
干扰素基因刺激因子(stimulator of interferon genes,STING)是cGAS-STING信号通路中的关键蛋白,在外源或内源DNA介导的免疫应答中发挥着重要作用。该篇综述对STING的生物学功能,cGAS-STING通路发挥作用的过程,以及STING激动剂的分类和...干扰素基因刺激因子(stimulator of interferon genes,STING)是cGAS-STING信号通路中的关键蛋白,在外源或内源DNA介导的免疫应答中发挥着重要作用。该篇综述对STING的生物学功能,cGAS-STING通路发挥作用的过程,以及STING激动剂的分类和给药方式进行了介绍,并总结了目前已报道的药物递送系统。采用适当的药物载体递送STING激动剂可以克服其入胞困难、易被酶解、半衰期短和靶向性差的不足,提高机体的固有免疫和适应性免疫刺激,从而增强药物的治疗效果。总之,该文主要针对STING激动剂释药系统的研究进展进行综述,以期为其递送系统的开发提供依据,推动STING激动剂的临床转化和应用。展开更多
Cyclic dinucleotides(CDNs)as stimulator of interferon genes(STING)agonists capable of inducing strong antitumor innate immune response are highly promising for tumor immunotherapy.The efficacy of these CDNs is,however...Cyclic dinucleotides(CDNs)as stimulator of interferon genes(STING)agonists capable of inducing strong antitumor innate immune response are highly promising for tumor immunotherapy.The efficacy of these CDNs is,however,reduced greatly by their fast clearance,poor cell uptake and inefficient cytosolic transportation.Here,we report that reduction-responsive biodegradable chimaeric polymersomes(CPs)markedly enhance tumor retention and cytosolic delivery of a synthetic CDN,ADU-S100,and bolster STING pathway activation in the tumor microenvironment and tumor draining lymph nodes,giving significantly better tumor repression and survival of B16F10 melanoma-bearing mice compared with free CDN control.The superiority of CPs-mediated CDN delivery is further verified in combination therapy with low-dose fractionated radiation,which brings about clearly stronger and longer-term immunotherapeutic effects and protection against tumor re-challenge.The development of nano-STING agonists that are able to overcome the delivery barriers of CDNs represents an effective strategy to potentiate cancer immunotherapy.展开更多
Background： The CD38/cyclic ADP-ribose （cADPR） pathway plays a role in various central nervous system diseases and in morphine tolerance, but its role in local anesthetic intoxication is unknown. The aim of this st...Background： The CD38/cyclic ADP-ribose （cADPR） pathway plays a role in various central nervous system diseases and in morphine tolerance, but its role in local anesthetic intoxication is unknown. The aim of this study was to determine the role of the CD38/cADPR pathway in ropivacaine-induced convulsion. Methods： Forty male Sprague-Dawley rats were randomly divided into five groups （n = 8 per group）： sham group, ropivacaine group, ropivacaine＋8-Br-cADPR （5 nmol） group, ropivacaine＋8-Br-cADPR （10 nmol） group, and ropivacaine＋8-Br-cADPR （20 nmol） group （no rats died）. Rats were intracerebroventricularly injected with normal saline or 8-Br-cADPR 30 min before receiving an intraperitoneal injection of ropivacaine. Electroencephalography and convulsion behavior scores were recorded. The hippocampus was harvested from each group and subjected to nicotinamide adenine dinucleotide and cADPR assays, Western blotting analysis, and malondialdehyde （MDA） and superoxide dismutase （SOD） assays. Results： Intraperitoneal injection of ropivacaine （33.8 mg/kg） induced convulsions in rats. CD38 and cADPR levels increased significantly following ropivacaine-induced convulsion （P = 0.031 and 0.020, respectively, compared with the sham group）. Intraventricular injection of 8-Br-cADPR （5, 10, and 20 nmol） significantly prolonged convulsion latency （P = 0.037, 0.034, and 0.000, respectively）, reduced convulsion duration （P = 0.005, 0.005, and 0.005, respectively）, and reduced convulsion behavior scores （P = 0.015, 0.015, and 0.000, respectively）. Intraventricular injection of 8-Br-cADPR （10 nmol） also increased the B-cell lymphoma-2 （Bcl-2）/Bcl-2-associated X protein ratio （P = 0.044） and reduced cleaved Caspase 3/Caspase 3 ratio, inducible nitric oxide synthase, MDAand SOD levels （P = 0.014, 0.044, 0.001, and 0.010, respectively） compared with the ropivacaine group. Conclusions： The CD38/cADPR pathway is activated in ropivacaine-induced convulsion. Inhibiting this pathway alleviates ropivacaine-induced convulsion and protects the brain from apoptosis and oxidative stress.展开更多
The concept advanced by Berridge and colleagues that intracellular Ca2+-stores can be mobilized in an agonist-dependent and messenger(IP3)-mediated manner has put Ca 2+-mobilization at the center stage of signal trans...The concept advanced by Berridge and colleagues that intracellular Ca2+-stores can be mobilized in an agonist-dependent and messenger(IP3)-mediated manner has put Ca 2+-mobilization at the center stage of signal transduction mechanisms.During the late 1980s,we showed that Ca2+-stores can be mobilized by two other messengers unrelated to inositol trisphosphate(IP 3) and identified them as cyclic ADP-ribose(cADPR),a novel cyclic nucleotide from NAD,and nicotinic acid adenine dinucleotide phosphate(NAADP),a linear metabolite of NADP.Their messenger functions have now been documented in a wide range of systems spanning three biological kingdoms.Accumulated evidence indicates that the target of cADPR is the ryanodine receptor in the sarco/endoplasmic reticulum,while that of NAADP is the two pore channel in endolysosomes. As cADPR and NAADP are structurally and functionally distinct,it is remarkable that they are synthesized by the same enzyme.They are thus fraternal twin messengers.We first identified the Aplysia ADP-ribosyl cyclase as one such enzyme and,through homology,found its mammalian homolog,CD38.Gene knockout in mice confirms the important roles of CD38 in diverse physiological functions from insulin secretion,susceptibility to bacterial infection,to social behavior of mice through modulating neuronal oxytocin secretion.We have elucidated the catalytic mechanisms of the Aplysia cyclase and CD38 to atomic resolution by crystallography and site-directed mutagenesis.This article gives a historical account of the cADPR/NAADP/CD38-signaling pathway and describes current efforts in elucidating the structure and function of its components.展开更多
Stimulator of interferon genes,namely STING,an adaptor protein located in the endoplasmic reticulum,has been recognized as a shining target for cancer and infection research.However,STING agonists cyclic dinucleotides...Stimulator of interferon genes,namely STING,an adaptor protein located in the endoplasmic reticulum,has been recognized as a shining target for cancer and infection research.However,STING agonists cyclic dinucleotides(CDNs)have shown almost zero efficacy in phase I clinical trials as a monotherapy,likely due to poor cellular permeability and rapid diffusion despite intratumoral injection.These deficiencies further affect other applications of CDNs,such as pandemic SARS-CoV-2 prevention and therapy.Here,we rationally design a supramolecular cytosolic delivery system based on controllable recognition of calixarene,namely CASTING(CAlixarene-STING),to improve CDN druggability,including degradation stability,cellular permeability,and tissue retention.CASTING efficiently enhances the immunostimulatory potency of CDGSF[a chemically modified cyclic di-GMP(CDG)]to generate an immunogenic microenvironment for melanoma regression,anti-PD-1 response rate increase,and durable memory formation against tumor recurrence.More importantly,CASTING displays a superior adjuvant activity on SARSCoV-2 recombinant spike/receptor binding domain vaccines,inducing robust and coordinated T-cell and antibody responses against SARS-CoV-2 infection in vivo.Collectively,the CASTING design represents an innovative advancement to facilitate the clinical translational capability of STING agonists.展开更多
基金the National Key R&D Program of China(grant nos.2019YFA0904200 and 2018YFA0507600)the National Natural Science Foundation of China(grant nos.22237003 and 92053108)the Tsinghua University Spring Breeze Fund(grant no.2020Z99CFY042).
文摘Cyclic dinucleotides(CDNs)are natural agonists of the stimulator of interferon genes(STING),which is an attractive immunotherapy target.Currently,CDNs and their derivatives are being investigated clinically.However,the poor bioavailability of exogenous CDNs has limited their application in immunotherapy.Although nanocarriers are widely used for cytosolic delivery of CDNs,their loading capacity is insufficient,and their complicated composition and purification process raises bio-compatibility concerns.Herein,we report a super-simplified CDN self-assembly strategy for carrier-free delivery of CDNs.In the presence of excess K^(+),CDNs form oligomers which further self-assemble with divalent metal ions(such as Mn^(2+))to form nanoparticles(NPs)in aqueous solution.We demonstrate that the self-assembled CDN NPs promote cellular uptake of CDNs and enhance tumor immunogenicity by remodeling the tumor microenvironment,inducing immunogenic tumor cell death and increasing tumorinfiltrating lymphocytes,which is conducive to the generation of tumor neoantigen-specific T-cell responses.We also demonstrate that the use of CDN NPs alone or in combination with immune checkpoint blockades inhibits tumor growth,highlighting the fact that CDN NPs are a potent platform for cancer immunotherapy.
基金the National Key Research and Development Program of China(Grant Nos.2022YFC3401500 and 2020YFA0803201 to P.W.,and 2021YFA1302200 to L.F.)the National Natural Science Foundation of China(Grant Nos.31830053,31920103007,and 82341028 to P.W.+1 种基金82122056,82073153,and 31871398 to L.F.and 31900568 to P.W.)the Natural Science Foundation of Shanghai(Grant No.22ZR1450700 to Z.J.W.)。
文摘The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer treatment.Within this landscape,the innate immune system,a critical sentinel protecting against tumor incursion,is a key player.The cyclic GMP-AMP synthase(c GAS)and stimulator of interferon genes(STING)pathway has been found to be a linchpin of innate immunity:activation of this signaling pathway orchestrates the production of type I interferon(IFN-α/β),thus fostering the maturation,differentiation,and mobilization of immune effectors in the tumor microenvironment.Furthermore,STING activation facilitates the release and presentation of tumor antigens,and therefore is an attractive target for cancer immunotherapy.Current strategies to activate the STING pathway,including use of pharmacological agonists,have made substantial advancements,particularly when combined with immune checkpoint inhibitors.These approaches have shown promise in preclinical and clinical settings,by enhancing patient survival rates.This review describes the evolving understanding of the c GAS-STING pathway's involvement in tumor biology and therapy.Moreover,this review explores classical and non-classical STING agonists,providing insights into their mechanisms of action and potential for optimizing immunotherapy strategies.Despite challenges and complexities,the c GAS-STING pathway,a promising avenue for enhancing cancer treatment efficacy,has the potential to revolutionize patient outcomes.
基金the National Key Research and Development Program of China(2017YFD0200500)the National Natural Science Foundation of China(21740002,21837001)。
文摘Cyclic dinucleotides(CDNs) are known to activate stimulator of interferon genes(STING) and induce type I interferon responses, therefor possess great potentials to be of immunotherapeutic value for cancers and infectious diseases. However, the existence of different single nucleotide polymorphism(SNP) of human STING(hSTING) gene poses an obstacle to achieve broad-spectrum activation by CDNs. We reported here the design and synthesis of a total of 36 CDNs, representing all structural variations, that contain four bases(A, G, C, U) and two linkage directions(2′-5′-linked and 3′-5′-linked phosphodiester).Through systematic evaluation of IFN-β induction with a dual-luciferase reporter assay, we discovered that wild type hSTING and two isoforms(HAQ and AQ) showed strong response while hSTING-R232 H and R293 Q exhibited the relatively weak response to CDNs stimulation. For the first time, we found that the c[G(2′,5′)U(2′,5′)] showed excellent activity against all five hSTING variants even equivalent to the endogenous ligand c[G(2′,5′)A(3′,5′)]. Furthermore, we have also demonstrated that 3′-3′CDNs with two 3′-5′ phosphodiesters showed higher serum and hydrolase stability than 2′-2′ CDNs with two 2′-5′ phosphodiesters and 2′-3′ CDNs with one 2′-5′ and one 3′-5′ phosphodiester. It is very interesting to note that 2′-2′ CDNs has been found for the first time to show strong activity. These findings will stimulate our exploration for the new functional role of CDNs, and provide guidelines to design CDNs based hSTING targeted drugs.
文摘An NAD analogue, N-(2-thiol-ethyl)-nicotinamide (TENA), was synthesized. TENA was used to modify the Au electrode through self-assembled monolayer.The cyclic voltammetry study of the electrode was carried out. The interference of dimerization of the NAD analogues reported in the literature was successfully avoided. The results support a mechanism of an electron transfer followed by chemical reaction during part of the redox process of TENA. Some useful reaction parameters were obtained.
文摘干扰素基因刺激因子(stimulator of interferon genes,STING)是cGAS-STING信号通路中的关键蛋白,在外源或内源DNA介导的免疫应答中发挥着重要作用。该篇综述对STING的生物学功能,cGAS-STING通路发挥作用的过程,以及STING激动剂的分类和给药方式进行了介绍,并总结了目前已报道的药物递送系统。采用适当的药物载体递送STING激动剂可以克服其入胞困难、易被酶解、半衰期短和靶向性差的不足,提高机体的固有免疫和适应性免疫刺激,从而增强药物的治疗效果。总之,该文主要针对STING激动剂释药系统的研究进展进行综述,以期为其递送系统的开发提供依据,推动STING激动剂的临床转化和应用。
基金supported by research grants from the National Natural Science Foundation of China(NSFC 52033006,51861145310,51773146 and 51633005)and the National Key R&D Program of China(2021YFB3800900).
文摘Cyclic dinucleotides(CDNs)as stimulator of interferon genes(STING)agonists capable of inducing strong antitumor innate immune response are highly promising for tumor immunotherapy.The efficacy of these CDNs is,however,reduced greatly by their fast clearance,poor cell uptake and inefficient cytosolic transportation.Here,we report that reduction-responsive biodegradable chimaeric polymersomes(CPs)markedly enhance tumor retention and cytosolic delivery of a synthetic CDN,ADU-S100,and bolster STING pathway activation in the tumor microenvironment and tumor draining lymph nodes,giving significantly better tumor repression and survival of B16F10 melanoma-bearing mice compared with free CDN control.The superiority of CPs-mediated CDN delivery is further verified in combination therapy with low-dose fractionated radiation,which brings about clearly stronger and longer-term immunotherapeutic effects and protection against tumor re-challenge.The development of nano-STING agonists that are able to overcome the delivery barriers of CDNs represents an effective strategy to potentiate cancer immunotherapy.
文摘Background： The CD38/cyclic ADP-ribose （cADPR） pathway plays a role in various central nervous system diseases and in morphine tolerance, but its role in local anesthetic intoxication is unknown. The aim of this study was to determine the role of the CD38/cADPR pathway in ropivacaine-induced convulsion. Methods： Forty male Sprague-Dawley rats were randomly divided into five groups （n = 8 per group）： sham group, ropivacaine group, ropivacaine＋8-Br-cADPR （5 nmol） group, ropivacaine＋8-Br-cADPR （10 nmol） group, and ropivacaine＋8-Br-cADPR （20 nmol） group （no rats died）. Rats were intracerebroventricularly injected with normal saline or 8-Br-cADPR 30 min before receiving an intraperitoneal injection of ropivacaine. Electroencephalography and convulsion behavior scores were recorded. The hippocampus was harvested from each group and subjected to nicotinamide adenine dinucleotide and cADPR assays, Western blotting analysis, and malondialdehyde （MDA） and superoxide dismutase （SOD） assays. Results： Intraperitoneal injection of ropivacaine （33.8 mg/kg） induced convulsions in rats. CD38 and cADPR levels increased significantly following ropivacaine-induced convulsion （P = 0.031 and 0.020, respectively, compared with the sham group）. Intraventricular injection of 8-Br-cADPR （5, 10, and 20 nmol） significantly prolonged convulsion latency （P = 0.037, 0.034, and 0.000, respectively）, reduced convulsion duration （P = 0.005, 0.005, and 0.005, respectively）, and reduced convulsion behavior scores （P = 0.015, 0.015, and 0.000, respectively）. Intraventricular injection of 8-Br-cADPR （10 nmol） also increased the B-cell lymphoma-2 （Bcl-2）/Bcl-2-associated X protein ratio （P = 0.044） and reduced cleaved Caspase 3/Caspase 3 ratio, inducible nitric oxide synthase, MDAand SOD levels （P = 0.014, 0.044, 0.001, and 0.010, respectively） compared with the ropivacaine group. Conclusions： The CD38/cADPR pathway is activated in ropivacaine-induced convulsion. Inhibiting this pathway alleviates ropivacaine-induced convulsion and protects the brain from apoptosis and oxidative stress.
基金supported by the Research Grants Council of Hong Kong(Grant Nos.769107,768408, 769309 and 770610)the National Natural Science Foundation of China/the Research Grants Council of Hong Kong(Grant No.N_HKU 722/08)
文摘The concept advanced by Berridge and colleagues that intracellular Ca2+-stores can be mobilized in an agonist-dependent and messenger(IP3)-mediated manner has put Ca 2+-mobilization at the center stage of signal transduction mechanisms.During the late 1980s,we showed that Ca2+-stores can be mobilized by two other messengers unrelated to inositol trisphosphate(IP 3) and identified them as cyclic ADP-ribose(cADPR),a novel cyclic nucleotide from NAD,and nicotinic acid adenine dinucleotide phosphate(NAADP),a linear metabolite of NADP.Their messenger functions have now been documented in a wide range of systems spanning three biological kingdoms.Accumulated evidence indicates that the target of cADPR is the ryanodine receptor in the sarco/endoplasmic reticulum,while that of NAADP is the two pore channel in endolysosomes. As cADPR and NAADP are structurally and functionally distinct,it is remarkable that they are synthesized by the same enzyme.They are thus fraternal twin messengers.We first identified the Aplysia ADP-ribosyl cyclase as one such enzyme and,through homology,found its mammalian homolog,CD38.Gene knockout in mice confirms the important roles of CD38 in diverse physiological functions from insulin secretion,susceptibility to bacterial infection,to social behavior of mice through modulating neuronal oxytocin secretion.We have elucidated the catalytic mechanisms of the Aplysia cyclase and CD38 to atomic resolution by crystallography and site-directed mutagenesis.This article gives a historical account of the cADPR/NAADP/CD38-signaling pathway and describes current efforts in elucidating the structure and function of its components.
基金supported by the National Key R&D Program of China(nos.2019YFA0904200 and 2018YFA0507600)the Tsinghua University Spring Breeze Fund(no.2020Z99CFY042)+1 种基金the National Natural Science Foundation of China(nos.92053108 and 31961143004)NCC Fund(no.NCC2020FH04).
文摘Stimulator of interferon genes,namely STING,an adaptor protein located in the endoplasmic reticulum,has been recognized as a shining target for cancer and infection research.However,STING agonists cyclic dinucleotides(CDNs)have shown almost zero efficacy in phase I clinical trials as a monotherapy,likely due to poor cellular permeability and rapid diffusion despite intratumoral injection.These deficiencies further affect other applications of CDNs,such as pandemic SARS-CoV-2 prevention and therapy.Here,we rationally design a supramolecular cytosolic delivery system based on controllable recognition of calixarene,namely CASTING(CAlixarene-STING),to improve CDN druggability,including degradation stability,cellular permeability,and tissue retention.CASTING efficiently enhances the immunostimulatory potency of CDGSF[a chemically modified cyclic di-GMP(CDG)]to generate an immunogenic microenvironment for melanoma regression,anti-PD-1 response rate increase,and durable memory formation against tumor recurrence.More importantly,CASTING displays a superior adjuvant activity on SARSCoV-2 recombinant spike/receptor binding domain vaccines,inducing robust and coordinated T-cell and antibody responses against SARS-CoV-2 infection in vivo.Collectively,the CASTING design represents an innovative advancement to facilitate the clinical translational capability of STING agonists.
