Review Series
Abstract
Immunotherapy has revolutionized the therapeutic landscape for many cancers, but its application in solid tumors has lagged. There is now evidence that immunotherapy can improve outcomes in triple-negative breast cancer, but hormone receptor–positive (HR+) breast cancer has traditionally been considered immunologically cold. However, emerging evidence challenges this binary paradigm, suggesting that a biologically relevant subset of HR+/human epidermal growth factor receptor 2–negative (HER2–) tumors exhibit meaningful immunogenic features and clinically relevant sensitivity to immune-based treatment. In this Review we summarize the current understanding of immunogenicity and clinical use of immune-based treatments across breast cancer subtypes. We argue for a broader view of a spectrum of breast cancer immunogenicity and highlight the importance of host factors, including parity and lactation history, in shaping antitumor immunity. Improved identification of immunologically active subsets and deeper mechanistic insight will be essential to expand the therapeutic benefit of immunotherapy to broader patient cohorts and to refine care of patients with breast cancer.
Authors
Jasmine Kay, Julia R. Dixon-Douglas, Michael A. Harris, Courtney T. van Geelen, Sherene Loi
Abstract
Homologous recombination repair deficiency (HRD) occurs in approximately 10% of breast tumors and represents a major targetable vulnerability across multiple cancer types. Impairment of the homologous recombination DNA repair pathway — arising through somatic and germline mutations in homologous recombination repair genes, epigenetic mechanisms, and transcriptomic changes — leads to genomic instability and a reliance on error-prone repair mechanisms. Poly (ADP-ribose) polymerase (PARP) inhibitors harness the synthetic lethality of HRD and PARP inhibition, with current approvals encompassing both early-stage and advanced breast cancer in patients with germline BRCA1/2 (gBRCA1/2) mutations. However, emerging evidence suggests efficacy of PARP inhibitors beyond gBRCA1/2-mutated breast cancer to tumors with other homologous recombination repair defects that confer a “BRCAness” phenotype. This Review examines opportunities to broaden the use of PARP inhibitors in breast cancer and underscores the importance of innovative biomarkers, combination strategies, and next-generation agents to maximize therapeutic impact.
Authors
Charlotte S. Walmsley, Adela Rodriguez, Panagiotis A. Konstantinopoulos, Geoffrey I. Shapiro, Sara M. Tolaney, Judy E. Garber, Filipa Lynce
Abstract
Despite growing recognition of invasive lobular carcinoma (ILC) as a biologically and clinically distinct subtype of breast cancer, ILC remains understudied. Most contemporary therapeutic trials continue to enroll patients predominantly with invasive ductal carcinoma/invasive carcinoma of no special type and rarely stratify by histology. As a result, ILC’s unique disease biology, characteristic loss of E-cadherin function, diffuse growth pattern, and distinct metastatic tropism remain underrepresented in evidence that guides systemic therapy recommendations. In this Review, we examine key molecular alterations and emerging therapeutic targets in ILC, emphasizing recent preclinical discoveries that identify subtype-specific therapeutic vulnerabilities and guide the development of histology-specific treatment approaches for this unique disease. In combination with endocrine therapies, effective targeting in ILC may require a multilayered strategy that extends beyond genomic alterations to leverage ILC’s specific estrogen receptor–associated proteins, metabolism, and tumor microenvironment. Future clinical trial frameworks incorporating prespecified ILC cohorts, tailored endpoints, and coclinical approaches enabling parallel testing in patients and patient-derived models could help accelerate the development and evaluation of ILC-targeted therapeutics.
Authors
Kristina A. Fanucci, Shaymaa Bahnassy, Arya Mariam Roy, Anna Sokolova, Daniel G. Stover, Peter T. Simpson, Rebecca B. Riggins, Rinath Jeselsohn
Abstract
Antibody-drug conjugates (ADCs) have transformed the treatment landscape of breast cancer and redefined the conceptual distinction between targeted therapy and conventional chemotherapy. Originally conceived as “magic bullets” that selectively deliver cytotoxic warheads to antigen-expressing tumor cells, clinical and mechanistic evidence indicates that ADC activity depends on a broader interplay of target-dependent and target-independent mechanisms, including extracellular payload release, bystander killing, off-tumor uptake, and immune modulation. Here, we examine ADCs in breast cancer as a distinct therapeutic paradigm. We discuss how antigen biology, linker chemistry, payload features, and drug-to-antibody ratio collectively determine efficacy, toxicity, and therapeutic index. We then compare currently approved and emerging HER2- and TROP2-directed ADCs, highlighting how differences in linker stability, payload pharmacology, and bystander capacity can affect clinical outcomes in ADCs sharing the same target. We further discuss the biological basis and translational challenges of de novo and acquired resistance related to targets, payloads, and tumor microenvironmental constraints, as well as the implications of these mechanisms for biomarker development, sequencing rationales, and combination strategies with immune checkpoint inhibitors and DNA repair–targeting therapies. Finally, we outline future directions of ADC development, including expansion of the target space, novel payload modalities, and next-generation antibody and conjugation engineering.
Authors
Chenxu Guo, Leif W. Ellisen
Abstract
Regulation of mitochondrial health is critical for maintaining cellular homeostasis in the nervous system. Damaged mitochondria can have detrimental effects on neuronal health and are thought to be key contributors to the progression of neurodegenerative disorders including Parkinson’s disease and amyotrophic lateral sclerosis. To mitigate this damage, multiple quality control mechanisms have evolved to eliminate aged or damaged mitochondria. One such quality control process is autophagy, a process that involves turnover of mitochondria at presynaptic sites and the axon terminal under basal conditions. This highly conserved mechanism sequesters mitochondria from the cytosol within autophagosomes followed by degradation upon fusion with a lysosome. Acute mitochondrial damage activates a selective form of autophagy called mitophagy that involves receptor-mediated engulfment and degradation of the damaged organelle. Multiple mechanisms have been shown to drive efficient mitophagy in neurons and glia, including PTEN induced kinase 1 (PINK1)/Parkin–dependent mitophagy and receptor-mediated mitophagy. Genetic, pathological, and experimental evidence all implicate defects in the removal of damaged mitochondria in the onset or progression of neurodegenerative disease. Both the initiation of PINK1/Parkin–dependent mitophagy and deficits in the removal of damaged mitochondria are linked to activation of neuroinflammatory pathways, including NF-κB and cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) signaling. In this Review, we discuss the molecular pathways governing mitophagy in neurons and glial cells and how deficits in these pathways may lead to neurodegeneration. We also highlight emerging therapeutic strategies aimed at restoring mitophagy to preserve neuronal homeostasis and function.
Authors
Bishal Basak, Julia F. Riley, Neha M. Nataraj, Erika L.F. Holzbaur
Abstract
The cGAS/STING pathway is a central innate immune DNA-sensing system that links aberrant DNA species to innate immune and stress-response transcriptional programs and has emerged as a key regulator of tumor-immune interactions. In cancer, pathway outputs are shaped by interconnected downstream signaling modules, including type I IFN, NF-κB, autophagy, and stress-metabolic checkpoints, as well as by stringent spatial and biochemical regulation of both cGAS and STING. When activation is acute and appropriately compartmentalized, cGAS/STING signaling promotes antitumor immunity across multiple cellular compartments in the tumor microenvironment, supporting DC cross-priming and cytotoxic lymphocyte responses. In contrast, chronic or dysregulated activation rewires downstream signaling toward stress-adaptive and inflammatory programs that promote tumor progression, metastasis, and immune dysfunction, including deleterious effects in lymphocytes and the induction of suppressive myeloid and B cell populations. Here, we examine how context determines the consequences of cGAS/STING activation in cancer, review emerging therapeutic strategies that modulate this pathway, and discuss how its antitumor potential can be maximized while minimizing systemic toxicity and immune dysregulation.
Authors
Yi Wang, Juan Angulo-Lozano, Yueqi Wang, Liang Deng
Abstract
Cardiovascular diseases (CVDs) remain the leading cause of mortality and morbidity worldwide, highlighting the need for novel therapeutic approaches. Inflammation plays a key role in CVD pathogenesis, and accumulating evidence has implicated the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway in this process. The cGAS/STING pathway recognizes both non-self- and self-DNA, including mitochondrial and nuclear DNA, to activate its downstream proinflammatory signaling molecules, including TANK-binding kinase 1, IFN regulatory factor 3, and NF-κB. Various pathological stressors have been shown to induce self-DNA release into the cytosol and bloodstream from damaged cells in the cardiovascular system, indicating that circulating cell-free DNA is a useful biomarker of CVDs; however, how this contributes to the inflammatory signaling, cell death, and fibrosis that characterize CVDs remains unclear. Here, we discuss the current understanding on the roles of self-DNA and the cGAS/STING pathway in the pathophysiology of CVDs and the therapeutic potential of targeting this pathway.
Authors
Wataru Saitoh, Yasutomi Higashikuni, Oyunbileg Bavuu, Masataka Sata, Daiju Fukuda
Abstract
The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway is a central regulator of innate immunity that links cytosolic DNA sensing to type I IFN and inflammatory responses. While initially viewed as a uniformly beneficial antiviral and antitumor signaling axis, emerging evidence reveals that cGAS-STING functions as a context-dependent immune rheostat whose impact is dictated by signal magnitude, timing, cellular origin, subcellular localization of signaling components, and tissue context. These parameters explain why pathway activation can promote tumor rejection, vaccine efficacy, and host defense in some settings yet drive immune suppression, metastasis, neuroinflammation, or autoinflammatory disease in others. In this Review, we synthesize mechanistic and clinical insights across agonist and antagonist strategies targeting the cGAS-STING pathway in cancer, infectious disease, neurodegeneration, and interferonopathies. We highlight why first-generation STING agonists have underperformed clinically and how next-generation delivery systems and cGAS-directed approaches may overcome these limitations. We propose a disease-centric framework that integrates spatial delivery, dosing architecture, and pharmacodynamic biomarker discovery to enable rational modulation of cGAS-STING, repositioning the pathway as a tunable immunologic control node for precision therapy rather than a binary on/off switch.
Authors
Akanksha S. Mahajan, Connor M. Forsyth, Cao Dai Phung, Xinhe Shen, Rachel Jarvis, Alexander H. Stegh
Abstract
The cGAS/STING pathway enables cells to sense cytosolic DNA and mount rapid innate immune responses to infection, cellular stress, and tissue damage. While essential for host defense and immune surveillance, inappropriate or sustained activation of this pathway can drive chronic inflammation, autoimmunity, and disease-associated immune dysfunction, which can promote cancer growth. Effective immunity therefore depends on precise regulatory control that restrains cGAS/STING activity under homeostatic conditions while preserving the capacity for swift and robust responses to diverse danger signals. In this Review, we synthesize emerging principles that regulate cGAS/STING signaling across cellular contexts to control signal initiation, amplification, and termination. We discuss how disruption, persistence, or pathological rewiring of these regulatory processes contributes to immune imbalance across health and disease, promoting chronic inflammation, immunosuppression, and tissue pathology, with particular relevance to tumor progression and therapeutic resistance. Finally, we consider how restoring appropriate cGAS/STING regulation, rather than simply enhancing or inhibiting pathway activity, may reestablish immune homeostasis and improve therapeutic outcomes in cancer and other inflammatory diseases, framing the pathway as a dynamic regulatory circuit rather than a simple linear signaling cascade.
Authors
Min-Guk Cho, Rachel Lee, Jaycee Johnson, Gaorav P. Gupta
Abstract
Breakthroughs in rare genetic disease research elucidate the relationships among cytosolic DNA sensing, genome instability, and autoimmune disease phenotypes. Cytosolic self-DNA is a potent trigger of innate immunity, activating the DNA sensor cyclic GMP-AMP synthase (cGAS) and its downstream effector stimulator of interferon genes (STING). This pathway is negatively regulated by the DNA-degrading enzyme three-prime repair exonuclease 1 (TREX1); loss-of-function TREX1 variants lead to accumulation of cytosolic DNA, resulting in STING-mediated autoinflammation. Similarly, STING gain-of-function mutations cause STING-associated vasculopathy with onset in infancy, another disease characterized by multi-organ damage, disability, and premature death. The TREX1-cGAS-STING pathway has also been implicated in regulation of genome stability. Indeed, DNA damage lies at the heart of a separate TREX1-mediated disease, known as retinal vasculopathy with cerebral leukoencephalopathy, where the aberrant nuclear activity of mislocalized TREX1 damages genomic DNA, resulting in multi-organ degeneration syndrome with features of autoimmunity. Thus, monogenic autoimmune diseases and DNA damage syndromes sometimes overlap clinically, and the study of these diseases has created pathways for developing first-in-class small molecule therapeutics.
Authors
Debby J. Park, Kate M. Jones, Jessica B. Anderson, Amanda V. Finck, Jonathan J. Miner
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ISSN: 0021-9738 (print), 1558-8238 (online)