Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy

Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma

(2020) Lihong Wang-Bishop et al.   Journal for ImmunoTherapy of Cancer

Small molecules targeting the innate immune cGAS‒STING‒TBK1 signaling pathway

(2020) Chunyong Ding et al.   Acta Pharmaceutica Sinica B

Overcoming resistance to STING agonist therapy to incite durable protective antitumor immunity

(2020) Henrique Lemos et al.   Journal for ImmunoTherapy of Cancer

Endosomolytic polymersomes increase the activity of cyclic dinucleotide STING agonists to enhance cancer immunotherapy

(2019) Daniel Shae et al.   Nature Nanotechnology

Pharmacological Modulation of the STING Pathway for Cancer Immunotherapy

(2019) Gilles Berger et al.   TRENDS IN MOLECULAR MEDICINE

Structural basis of STING binding with and phosphorylation by TBK1

(2019) Conggang Zhang et al.   NATURE

Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP–AMP

(2019) Guijun Shang et al.   NATURE

Phase Ib study of MIW815 (ADU-S100) in combination with spartalizumab (PDR001) in patients (pts) with advanced/metastatic solid tumors or lymphomas.

(2019) Funda Meric-Bernstam et al.   JOURNAL OF CLINICAL ONCOLOGY

SLC19A1 Is an Importer of the Immunotransmitter cGAMP

(2019) Christopher Ritchie et al.   MOLECULAR CELL

A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1

(2019) Baoyu Zhao et al.   NATURE

Discovery and Mechanistic Study of a Novel Human-Stimulator-of-Interferon-Genes Agonist

(2019) Xiaohui Zhang et al.   ACS Infectious Diseases

A microparticle platform for STING-targeted immunotherapy enhances natural killer cell- and CD8+ T cell-mediated anti-tumor immunity

(2019) Rebekah Watkins-Schulz et al.   BIOMATERIALS

The cGAS-STING pathway is a therapeutic target in a preclinical model of hepatocellular carcinoma

(2019) Martin K. Thomsen et al.   ONCOGENE

The triggers of the cGAS-STING pathway and the connection with inflammatory and autoimmune diseases

(2019) Ruoyu Zhou et al.   INFECTION GENETICS AND EVOLUTION

Agonists and inhibitors of the STING pathway: Potential agents for immunotherapy

(2019) Jun‐Jun Wu et al.   MEDICINAL RESEARCH REVIEWS

The Cytosolic DNA-Sensing cGAS–STING Pathway in Cancer

(2019) John Kwon et al.   Cancer Discovery

STINGel: Controlled release of a cyclic dinucleotide for enhanced cancer immunotherapy

(2018) David G. Leach et al.   BIOMATERIALS

Dynamic Structural Differences between Human and Mouse STING Lead to Differing Sensitivity to DMXAA

(2018) Amy Y. Shih et al.   BIOPHYSICAL JOURNAL

Mechanisms of resistance to immune checkpoint inhibitors

(2018) Russell W Jenkins et al.   BRITISH JOURNAL OF CANCER

Extrinsic Phagocyte-Dependent STING Signaling Dictates the Immunogenicity of Dying Cells

(2018) Jeonghyun Ahn et al.   CANCER CELL

Immune Checkpoint Blockade across the Cancer Care Continuum

(2018) Beth A. Helmink et al.   IMMUNITY

Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors

(2018) Kristian M. Hargadon et al.   INTERNATIONAL IMMUNOPHARMACOLOGY

The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer

(2018) Tuo Li et al.   JOURNAL OF EXPERIMENTAL MEDICINE

Biodegradable STING agonist nanoparticles for enhanced cancer immunotherapy

(2018) David R. Wilson et al.   Nanomedicine-Nanotechnology Biology and Medicine

Extended release of perioperative immunotherapy prevents tumor recurrence and eliminates metastases

(2018) Chun Gwon Park et al.   Science Translational Medicine

Evaluation of explant responses to STING ligands: personalized immunosurgical therapy for head and neck squamous cell carcinoma

(2018) Jason R. Baird et al.   CANCER RESEARCH

Identification of α-Mangostin as an Agonist of Human STING

(2018) Yibo Zhang et al.   ChemMedChem

LBA15Preliminary results of the first-in-human (FIH) study of MK-1454, an agonist of stimulator of interferon genes (STING), as monotherapy or in combination with pembrolizumab (pembro) in patients with advanced solid tumors or lymphomas

(2018) K J Harrington et al.   ANNALS OF ONCOLOGY

Tumor cGAMP Awakens the Natural Killers

(2018) Shriram K. Sundararaman et al.   IMMUNITY

Tumor-Derived cGAMP Triggers a STING-Mediated Interferon Response in Non-tumor Cells to Activate the NK Cell Response

(2018) Assaf Marcus et al.   IMMUNITY

Ovarian Cancer Cells Commonly Exhibit Defective STING Signaling Which Affects Sensitivity to Viral Oncolysis

(2018) Nina Marí Gual Pimenta de Queiroz et al.   MOLECULAR CANCER RESEARCH

Acetalated Dextran Microparticles for Codelivery of STING and TLR7/8 Agonists

(2018) Michael A. Collier et al.   MOLECULAR PHARMACEUTICS

Design of amidobenzimidazole STING receptor agonists with systemic activity

(2018) Joshi M. Ramanjulu et al.   NATURE

Suppression of STING Associated with LKB1 Loss in KRAS-Driven Lung Cancer

(2018) Shunsuke Kitajima et al.   Cancer Discovery

Magnitude of Therapeutic STING Activation Determines CD8+ T Cell-Mediated Anti-tumor Immunity

(2018) Kelsey E. Sivick et al.   Cell Reports

Nano-, micro-, and macroscale drug delivery systems for cancer immunotherapy

(2018) Pingsheng Huang et al.   Acta Biomaterialia

Cyclic dinucleotides modulate induced type I IFN responses in innate immune cells by degradation of STING

(2017) Christine Rueckert et al.   FASEB JOURNAL

Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors

(2017) Tyrel T. Smith et al.   JOURNAL OF CLINICAL INVESTIGATION

Cutting Edge: Activation of STING in T Cells Induces Type I IFN Responses and Cell Death

(2017) Bridget Larkin et al.   JOURNAL OF IMMUNOLOGY

De-novo and acquired resistance to immune checkpoint targeting

(2017) Nicholas L Syn et al.   LANCET ONCOLOGY

cGAS surveillance of micronuclei links genome instability to innate immunity

(2017) Karen J. Mackenzie et al.   NATURE

Mitotic progression following DNA damage enables pattern recognition within micronuclei

(2017) Shane M. Harding et al.   NATURE

Cytoplasmic chromatin triggers inflammation in senescence and cancer

(2017) Zhixun Dou et al.   NATURE

Radiotherapy and immunotherapy: a beneficial liaison?

(2017) Ralph R. Weichselbaum et al.   Nature Reviews Clinical Oncology

cGAS is essential for cellular senescence

(2017) Hui Yang et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Signalling strength determines proapoptotic functions of STING

(2017) Muhammet F. Gulen et al.   Nature Communications

Decreased expression of STING predicts poor prognosis in patients with gastric cancer

(2017) Shushu Song et al.   Scientific Reports

Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response

(2017) Vijay K. Gonugunta et al.   Cell Reports

Intratumoral STING Activation with T-cell Checkpoint Modulation Generates Systemic Antitumor Immunity

(2017) Casey R. Ager et al.   Cancer Immunology Research

A STING Agonist Given with OX40 Receptor and PD-L1 Modulators Primes Immunity and Reduces Tumor Growth in Tolerized Mice

(2017) Jeremy B. Foote et al.   Cancer Immunology Research

Submicron-sized hydrogels incorporating cyclic dinucleotides for selective delivery and elevated cytokine release in macrophages

(2016) Eunjoo Lee et al.   Acta Biomaterialia

Recurrent Loss of STING Signaling in Melanoma Correlates with Susceptibility to Viral Oncolysis

(2016) Tianli Xia et al.   CANCER RESEARCH

Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells

(2016) Chih-Hang Anthony Tang et al.   CANCER RESEARCH

STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation

(2016) Henrique Lemos et al.   CANCER RESEARCH

Degradable Controlled-Release Polymers and Polymeric Nanoparticles: Mechanisms of Controlling Drug Release

(2016) Nazila Kamaly et al.   CHEMICAL REVIEWS

Expansion and Activation of CD103 + Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition

(2016) Hélène Salmon et al.   IMMUNITY

Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors

(2016) Jonathan M. Pitt et al.   IMMUNITY

cGAS-cGAMP-STING: The three musketeers of cytosolic DNA sensing and signaling

(2016) Jianli Tao et al.   IUBMB LIFE

The host STING pathway at the interface of cancer and immunity

(2016) Leticia Corrales et al.   JOURNAL OF CLINICAL INVESTIGATION

Programmed Death-Ligand 1 Expression and Response to the Anti–Programmed Death 1 Antibody Pembrolizumab in Melanoma

(2016) Adil I. Daud et al.   JOURNAL OF CLINICAL ONCOLOGY

Carcinoma–astrocyte gap junctions promote brain metastasis by cGAMP transfer

(2016) Qing Chen et al.   NATURE

Type I/II Interferon Balance in the Regulation of Brain Physiology and Pathology

(2016) Aleksandra Deczkowska et al.   TRENDS IN IMMUNOLOGY

Activation of STING requires palmitoylation at the Golgi

(2016) Kojiro Mukai et al.   Nature Communications

Antitumor Activity of cGAMP via Stimulation of cGAS-cGAMP-STING-IRF3 Mediated Innate Immune Response

(2016) Tiejun Li et al.   Scientific Reports

Deregulation of STING Signaling in Colorectal Carcinoma Constrains DNA Damage Responses and Correlates With Tumorigenesis

(2016) Tianli Xia et al.   Cell Reports

Established T Cell-Inflamed Tumors Rejected after Adaptive Resistance Was Reversed by Combination STING Activation and PD-1 Pathway Blockade

(2016) E. Moore et al.   Cancer Immunology Research

Designing hydrogels for controlled drug delivery

(2016) Jianyu Li et al.   Nature Reviews Materials

Activated STING enhances Tregs infiltration in the HPV-related carcinogenesis of tongue squamous cells via the c-jun/CCL22 signal

(2015) Ding Liang et al.   BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

Nanoparticulate STING agonists are potent lymph node–targeted vaccine adjuvants

(2015) Melissa C. Hanson et al.   JOURNAL OF CLINICAL INVESTIGATION

Liposomes loaded with a STING pathway ligand, cyclic di-GMP, enhance cancer immunotherapy against metastatic melanoma

(2015) Takashi Nakamura et al.   JOURNAL OF CONTROLLED RELEASE

STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity

(2015) Olivier Demaria et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Neoantigens in cancer immunotherapy

(2015) T. N. Schumacher et al.   SCIENCE

The future of immune checkpoint therapy

(2015) P. Sharma et al.   SCIENCE

STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade

(2015) Juan Fu et al.   Science Translational Medicine

Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity

(2015) Leticia Corrales et al.   Cell Reports

Hydrogel: Preparation, characterization, and applications: A review

(2015) Enas M. Ahmed   Journal of Advanced Research

Nanoparticle-Based Immunotherapy for Cancer

(2014) Kun Shao et al.   ACS Nano

STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors

(2014) Seng-Ryong Woo et al.   IMMUNITY

A new adjuvant delivery system ‘cyclic di-GMP/YSK05 liposome’ for cancer immunotherapy

(2014) Hiroko Miyabe et al.   JOURNAL OF CONTROLLED RELEASE

STING-Mediated DNA Sensing Promotes Antitumor and Autoimmune Responses to Dying Cells

(2014) Jared Klarquist et al.   JOURNAL OF IMMUNOLOGY

Cutting Edge: STING Mediates Protection against Colorectal Tumorigenesis by Governing the Magnitude of Intestinal Inflammation

(2014) Qifan Zhu et al.   JOURNAL OF IMMUNOLOGY

PD-1 blockade induces responses by inhibiting adaptive immune resistance

(2014) Paul C. Tumeh et al.   NATURE

Hydrolysis of 2′3′-cGAMP by ENPP1 and design of nonhydrolyzable analogs

(2014) Lingyin Li et al.   Nature Chemical Biology

Activated STING in a Vascular and Pulmonary Syndrome

(2014) Yin Liu et al.   NEW ENGLAND JOURNAL OF MEDICINE

Inflammation-driven carcinogenesis is mediated through STING

(2014) Jeonghyun Ahn et al.   Nature Communications

Anticancer Flavonoids Are Mouse-Selective STING Agonists

(2013) Sujeong Kim et al.   ACS Chemical Biology

Structure-Function Analysis of STING Activation by c[G(2′,5′)pA(3′,5′)p] and Targeting by Antiviral DMXAA

(2013) Pu Gao et al.   CELL

Cyclic [G(2′,5′)pA(3′,5′)p] Is the Metazoan Second Messenger Produced by DNA-Activated Cyclic GMP-AMP Synthase

(2013) Pu Gao et al.   CELL

Species-specific detection of the antiviral small-molecule compound CMA by STING

(2013) Taner Cavlar et al.   EMBO JOURNAL

Oncology Meets Immunology: The Cancer-Immunity Cycle

(2013) Daniel S. Chen et al.   IMMUNITY

Cutting Edge: DNA Sensing via the STING Adaptor in Myeloid Dendritic Cells Induces Potent Tolerogenic Responses

(2013) L. Huang et al.   JOURNAL OF IMMUNOLOGY

Mouse, but not Human STING, Binds and Signals in Response to the Vascular Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid

(2013) J. Conlon et al.   JOURNAL OF IMMUNOLOGY

Cyclic GMP-AMP Containing Mixed Phosphodiester Linkages Is An Endogenous High-Affinity Ligand for STING

(2013) Xu Zhang et al.   MOLECULAR CELL

cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING

(2013) Andrea Ablasser et al.   NATURE

Innate and adaptive immune cells in the tumor microenvironment

(2013) Thomas F Gajewski et al.   NATURE IMMUNOLOGY

Delivery materials for siRNA therapeutics

(2013) Rosemary Kanasty et al.   NATURE MATERIALS

Single Nucleotide Polymorphisms of Human STING Can Affect Innate Immune Response to Cyclic Dinucleotides

(2013) Guanghui Yi et al.   PLoS One

Pivotal Roles of cGAS-cGAMP Signaling in Antiviral Defense and Immune Adjuvant Effects

(2013) X.-D. Li et al.   SCIENCE

Type I Interferons as Stimulators of DC-Mediated Cross-Priming: Impact on Anti-Tumor Response

(2013) Giovanna Schiavoni et al.   Frontiers in Immunology

Liposomal drug delivery systems: From concept to clinical applications

(2012) Theresa M. Allen et al.   ADVANCED DRUG DELIVERY REVIEWS

Carboplatin and Paclitaxel Plus ASA404 as First-Line Chemotherapy for Extensive-Stage Small-Cell Lung Cancer: A Multicenter Single Arm Phase II Trial (SAKK 15/08)

(2012) Martin Früh et al.   Clinical Lung Cancer

5,6-Dimethylxanthenone-4-acetic Acid (DMXAA) Activates Stimulator of Interferon Gene (STING)-dependent Innate Immune Pathways and Is Regulated by Mitochondrial Membrane Potential

(2012) Daniel Prantner et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

DNA breaks and chromosome pulverization from errors in mitosis

(2012) Karen Crasta et al.   NATURE

Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway

(2012) L. Sun et al.   SCIENCE

Type I interferon response and innate immune sensing of cancer

(2012) Mercedes B. Fuertes et al.   TRENDS IN IMMUNOLOGY

Hyaluronic Acid Hydrogels for Biomedical Applications

(2011) Jason A. Burdick et al.   ADVANCED MATERIALS

Hallmarks of Cancer: The Next Generation

(2011) Douglas Hanahan et al.   CELL

Prognostic significance of tumor-infiltrating T cells in ovarian cancer: A meta-analysis

(2011) Wei-Ting Hwang et al.   GYNECOLOGIC ONCOLOGY

Randomized Phase III Placebo-Controlled Trial of Carboplatin and Paclitaxel With or Without the Vascular Disrupting Agent Vadimezan (ASA404) in Advanced Non–Small-Cell Lung Cancer

(2011) Primo N. Lara et al.   JOURNAL OF CLINICAL ONCOLOGY

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer

(2011) Sahar M.A. Mahmoud et al.   JOURNAL OF CLINICAL ONCOLOGY

Host type I IFN signals are required for antitumor CD8+T cell responses through CD8α+dendritic cells

(2011) Mercedes B. Fuertes et al.   JOURNAL OF EXPERIMENTAL MEDICINE

STING is a direct innate immune sensor of cyclic di-GMP

(2011) Dara L. Burdette et al.   NATURE

Cancer immunotherapy – revisited

(2011) W. Joost Lesterhuis et al.   NATURE REVIEWS DRUG DISCOVERY

cAMP, c-di-GMP, c-di-AMP and now cGMP: bacteria use them all!

(2010) Mark Gomelsky   MOLECULAR MICROBIOLOGY

c-di-AMP Secreted by Intracellular Listeria monocytogenes Activates a Host Type I Interferon Response

(2010) J. J. Woodward et al.   SCIENCE

The potential of 3′,5′-cyclic diguanylic acid (c-di-GMP) as an effective vaccine adjuvant

(2010) Wangxue Chen et al.   VACCINE

Lipid-based systemic delivery of siRNA

(2009) Yu-Cheng Tseng et al.   ADVANCED DRUG DELIVERY REVIEWS

In Situ Cytotoxic and Memory T Cells Predict Outcome in Patients With Early-Stage Colorectal Cancer

(2009) Franck Pagès et al.   JOURNAL OF CLINICAL ONCOLOGY

A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP

(2009) Sarah M. McWhirter et al.   JOURNAL OF EXPERIMENTAL MEDICINE

Dendritic cells require a systemic type I interferon response to mature and induce CD4+Th1 immunity with poly IC as adjuvant

(2009) M. Paula Longhi et al.   JOURNAL OF EXPERIMENTAL MEDICINE

STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity

(2009) Hiroki Ishikawa et al.   NATURE

Immune infiltration in human tumors: a prognostic factor that should not be ignored

(2009) F Pagès et al.   ONCOGENE

Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor

(2008) Jean-Philippe Coppé et al.   PLOS BIOLOGY