Breast cancer, the most frequently occurring malignant tumor among women globally, poses a serious threat to patients’ health and quality of life and is also one of the leading causes of cancer-related deaths (1, 2). Its complexity lies in its heterogeneity, being composed of different subtypes with varying biological behaviors, morphological characteristics, and treatment responses. Based on molecular features, breast cancer is mainly divided into four subtypes: Luminal type (60-70%): including Luminal A (HR+/HER2-/low Ki-67) and Luminal B (HR+/high Ki-67); HER2+ type (20%): driven by HER2 overexpression leading to aggressive growth; Triple-negative breast cancer (TNBC) (10-15%): ER/PR/HER2-negative, with a high risk of recurrence and metastasis (3, 4). According to the NCCN treatment guidelines, endocrine therapy is a common treatment for ER-positive breast cancer patients, and anti-HER2 targeted therapy is recommended for HER2-positive patients (5). However, there is currently no specific targeted therapy for TNBC. Despite significant progress in diagnosis and treatment, including multi-modal strategies such as surgery, chemotherapy, radiotherapy, endocrine therapy, and targeted therapy, 20%-30% of patients may still develop metastatic disease (6, 7). Recently, immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1) have achieved breakthroughs in TNBC, with the KEYNOTE-355 trial showing that pembrolizumab combined with chemotherapy extended progression-free survival (PFS) from 5.6 to 9.7 months in advanced TNBC patients (6, 8, 9). However, immune therapy still faces significant challenges. The tumor microenvironment varies greatly among subtypes, with high T-cell infiltration but strong immunosuppression in TNBC; HER2+ type has STING pathway inhibition leading to trastuzumab resistance, and the Luminal type has AKT1 overactivation weakening immune response; systemic immune activation may also trigger cytokine storms or autoimmune reactions (10–12). However, due to tumor heterogeneity and the development of drug resistance, the long-term effects of these treatments are often limited. Therefore, identifying new therapeutic targets and developing effective strategies for metastatic breast cancer is crucial for improving patient prognosis and survival rates.

Immunotherapy has made significant strides in cancer treatment. Immune checkpoint inhibitors targeting PD-1/PD-L1 show promise across multiple malignancies (13, 14). As tumor immunotherapy gains precision and efficacy, interest in developing new approaches is rising. The cancer-immune system interaction is intricate and dynamic. While the immune system can combat tumors by identifying and eliminating abnormal cells, tumors can evade this response through mechanisms like PD-L1 upregulation and Treg recruitment (15, 16). cGAS is a cytosolic innate immune sensor of double-stranded DNA (dsDNA), which interacts with the sugar-phosphate backbone of dsDNA via positively charged amino acid residues, a process further facilitated by a conserved zinc ribbon (17). Activated cGAS synthesizes cGAMP using ATP and GTP, inducing conformational changes in the endoplasmic reticulum-resident STING protein and promoting its trafficking from the endoplasmic reticulum to the Golgi apparatus (18). The most common mechanism by which STING enhances antitumor immune function is through the induction of interferon and inflammatory cytokine production, thereby activating cytotoxic CD8+ T cells to promote adaptive immune responses (19). The cGAS-STING pathway, linking DNA damage to immune responses, plays a dual role in breast cancer (20). It can both enhance antitumor immunity and, when chronically activated, potentially drive immunosuppression (21). STING agonists can enhance antitumor immune responses, their combination with radiotherapy can boost complete response rates in TNBC (22). In HER2+ breast cancer, STING activation reverses trastuzumab resistance, and combination therapy with DS-8201 can extend median progression-free survival (mPFS). In the Luminal subtype, STING expression correlates with macrophage infiltration, yet chronic activation may expand Tregs, blunting therapeutic effects (23, 24).

cGAS-STING activation begins when cGAS detects cytosolic dsDNA, such as damage from radiotherapy or chemotherapy. This triggers a cascade: cGAS produces cGAMP, which activates STING, leading to IRF3 and NF-κB-driven expression of type I interferons and pro-inflammatory factors (25, 26). Beyond the classical cGAS-STING pathway characterized by IFN-I and other cytokine expression, non-canonical STING activation pathways should also be noted. STING can directly activate autophagy independently of TBK1-IRF3 and classical autophagy signaling molecules (27). When activated STING translocates to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), it acts as a potential autophagy receptor, using ERGIC as the primary membrane source to promote the lipidation of microtubule-associated LC3, inducing autophagy to eliminate invading pathogens and cytosolic DNA (28) ( Figure 1 ). Several STING agonists are now in clinical trials, showing potential in breast cancer. For example, in a phase I trial (NCT03937141) targeting advanced/metastatic solid tumors or lymphomas, researchers explored the combined therapeutic effects of the STING agonist ADU-S100 (MIW815) and the PD-1 inhibitor pembrolizumab. Results showed that this combination therapy could significantly enhance antitumor immune responses in certain patients, as evidenced by an increase in tumor-infiltrating lymphocytes (TILs) (30). MK-1454 in a phase II trial for HER2+ breast cancer extended mPFS by 3.1 months when combined with trastuzumab and chemotherapy, though with a 18% incidence of grade 3+ febrile neutropenia (31). These findings indicate that combining STING agonists with existing therapies may overcome resistance but require further safety optimization. By finely tuning cGAS-STING activity, we can enhance breast cancer immunogenicity and the efficacy of immune checkpoint inhibitors, offering more effective strategies for patients. Moreover, the link between cGAS-STING activation and genetic instability in breast cancer opens new avenues for personalized treatment strategies tailored to specific genetic backgrounds ( Figure 2 ).

This review systematically summarizes the pivotal roles of the cGAS-STING signaling pathway in breast cancer initiation, progression, drug resistance, and therapeutic responses, as well as its profound impact on tumor advancement and microenvironmental remodeling. The article delves into the intricate interplay between the activation status of the cGAS-STING pathway and the tumor immune microenvironment across distinct breast cancer subtypes, elucidating how these interactions may lead to divergent clinical outcomes—either beneficial or detrimental. Furthermore, the review critically examines current research directions and challenges associated with the cGAS-STING axis in breast cancer, while emphasizing recent breakthroughs in cGAS-STING-related studies. By integrating these insights, this work aims to deepen the mechanistic understanding of researchers and clinicians regarding the dual roles of cGAS-STING in breast cancer pathogenesis, ultimately paving the way for novel precision therapeutic strategies tailored to the molecular heterogeneity of the disease.

Breast cancer encompasses major subtypes, including Luminal, HER2+, and TNBC, each of which exhibits significant differences in response to treatment. The cGAS-STING pathway activates antitumor immunity by detecting cytoplasmic DNA, but its effects vary among subtypes. In the pathogenesis of breast cancer, the activation of the cGAS-STING signaling pathway plays a crucial role in enhancing antitumor immune responses, thereby suppressing the progression and metastasis of breast cancer, offering new potential strategies for immunotherapy in breast cancer (33). Cancer immunotherapy (ICI) is a key and rapidly evolving treatment modality that stands alongside surgical intervention, cytotoxic chemotherapy, radiotherapy, and targeted therapy (34). Thus, it represents the fifth pillar of cancer management. As our understanding of the molecular mechanisms and roles of the cGAS-STING pathway in breast cancer deepens, the development of new immunotherapeutic approaches is likely to benefit.

In recent years, research on the cGAS-STING pathway in breast cancer has made significant progress, and its regulatory mechanisms and clinical significance have become increasingly clear. Chen et al. systematically analyzed the prognostic value of cGAS-STING related genes (CSRG) in breast cancer patients by obtaining 1,087 breast cancer samples and 179 normal breast tissue samples from The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEX) databases, identifying 35 CSRGs. Further refinement using Cox regression identified 11 differentially expressed genes (DEGs) associated with prognosis, constructing a machine learning-based risk assessment and prognostic model. The study results indicate that this risk model can effectively predict the survival and prognosis of breast cancer patients, with patients having a low-risk score showing significantly better overall survival (OS) compared to those with a high-risk score (35).

Additionally, the study found a significant correlation between the risk score and tumor-infiltrating immune cells, immune checkpoints, and responses to immunotherapy, providing a new perspective for precision treatment and prognostic evaluation of breast cancer. The expression of the STING protein is closely related to the tumor microenvironment in breast cancer. In breast cancer tissues, the expression levels of STING are positively correlated with the infiltration of tumor-associated macrophages (TAMs), indicating that STING may affect tumor progression by regulating the infiltration of TAMs (36). Ka et al. showed that in breast cancer, NR1D1 promotes the accumulation of dsDNA fragments induced by DNA damage, activating the cGAS-STING signaling pathway, thereby increasing the production of type I IFN and downstream chemokines CCL5 and CXCL10 (37). Totis et al. have indicated that radiotherapy can trigger the activation of the cGAS-STING axis through the induction of cytoplasmic dsDNA fragments (38). The activation of cGAS-STING initiates type I interferon-mediated innate immune signaling, which is instrumental in eradicating malignant tumors (18). These findings reveal the potential of cGAS-STING pathway activation for anti-tumor immunity. Recently, there has been a growing interest in the activation of the cGAS-STING pathway through nanomaterials, providing new strategies for immunotherapy in breast cancer. However, Qin and others have shown that even in the presence of cytoplasmic DNA accumulation, hypoxia can induce an immunosuppressive phenotype in tumor cells (39). The mechanisms by which tumor cells suppress the activation of the cGAS-STING pathway induced by hypoxia to evade immunity are largely unclear. Research has shown that hypoxia stimulates JNK1/2-mediated phosphorylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at S151, a phosphorylation that triggers the interaction between PCK1 and cGAS. PCK1 associated with cGAS competitively consumes GTP, a substrate shared by PCK1 and cGAS. Consequently, PCK1 inhibits GTP-dependent cGAS activation and subsequent STING-promoted immune cell infiltration and activation in the tumor microenvironment, thereby promoting tumor growth in mice. Blocking PCK1 function in combination with anti-PD-1 antibody therapy exhibits an additive therapeutic effect on tumor growth (39). Furthermore, PCK1 S151 phosphorylation is negatively correlated with cGAS-STING activation and patient survival rates in human breast cancer specimens.

These findings reveal the complex mechanisms of the cGAS-STING pathway in breast cancer, showing both anti-tumor potential and the possibility of promoting tumor progression and drug resistance under certain conditions. Further exploration is needed to clarify the specific roles of the cGAS-STING pathway in different breast cancer subtypes and to develop targeted therapeutic strategies. In particular, modulating the cGAS-STING pathway to overcome immune suppression and drug resistance will be an important direction for breast cancer immunotherapy.

After reviewing and organizing a large number of relevant studies, we have gained a comprehensive understanding of the role of the cGAS-STING pathway in different breast cancer subtypes ( Table 1 ). Overall, this pathway plays a crucial role throughout the course of breast cancer, with its activation state closely linked to the tumor immune microenvironment. On one hand, activation of the pathway can enhance antitumor immune responses, opening new avenues for breast cancer immunotherapy. On the other hand, its sustained activation in certain contexts may lead to immunosuppression and drug resistance, negatively impacting treatment outcomes ( Figure 3 ). Specifically, in Luminal breast cancer hyperactivation of AKT kinase inhibits the formation of the STING-IRF3 complex by binding to TBK1, blocking IFN-I secretion and impairing immune surveillance. Concurrently, STING signaling inactivation further promotes AKT phosphorylation, forming a vicious cycle that drives endocrine therapy resistance. Endocrine resistance in Luminal breast cancer (particularly the ER+/HER2- subtype) remains a major research focus. Deng Rong’s team validated through clinical samples and humanized mouse models that combining STING agonists (e.g., ADU-S100) with AKT inhibitors (e.g., Capivasertib) breaks this cycle, significantly suppressing resistant tumor growth and promoting CD8+ T-cell infiltration, thereby converting “cold tumors” into “hot tumors”. However, chronic STING activation may upregulate PD-L1 expression via the IRF3 signaling axis and induce regulatory T-cell expansion, leading to an immunosuppressive microenvironment. The resistance mechanisms of STING agonists in Luminal breast cancer are complex, involving signaling pathway imbalances, metabolic abnormalities, and immune microenvironment remodeling, necessitating further research. In HER2-positive breast cancer, STING agonists (e.g., ADU-S100) activate the cGAS-STING pathway to promote IFN-I secretion, enhancing APC maturation and cross-presentation. However, PI3K/AKT pathway hyperactivity driven by PIK3CA mutations inhibits STING signaling by disrupting TBK1-STING interactions, blocking IFN-β secretion and enabling immune evasion. Preclinical studies in trastuzumab-resistant models demonstrate that combining STING agonists (e.g., ADU-S100) with HER2-targeted antibody-drug conjugates (e.g., DS-8201) significantly reduces the proportion of CD44+/CD24− cancer stem cells and enhances dendritic cell cross-presentation to promote CD8+ T-cell infiltration. The therapeutic challenges of TNBC stem from its high heterogeneity and immunosuppressive microenvironment. Current research focuses on manganese-based nanoagonists (e.g., BMP-Au), which activate the cGAS-STING pathway by inducing mitochondrial DNA release and synergize with radiotherapy to enhance immunogenic cell death, promoting CD8+ T-cell infiltration and significantly inhibiting TNBC lung metastasis. Combined with radiotherapy, this approach downregulates PD-L1 expression in the TME, reduces immunosuppressive myeloid-derived suppressor cells, and enhances antitumor immune responses. Additionally, GSH-responsive manganese oxide nanocubes activate both AMPK and STING pathways, inducing ferroptosis and immune responses to overcome chemoresistance. Mn²⁺release further activates the cGAS-STING pathway, promoting IFN-I secretion and APC function. However, studies also reveal that STING agonists may induce expansion of PD-L1^high monocytes via the IRF3-IFN-I axis, fostering an immunosuppressive microenvironment. TLR2 agonist pretreatment reprograms STING signaling by inducing K63 ubiquitination of STING, promoting its interaction with TRAF6, suppressing the IRF3-IFN-I axis, and activating the NF-κB pathway, thereby converting monocytes into PD-L1^low/– antitumor phenotypes. In breast cancer mouse models, combined TLR2/STING agonist therapy significantly inhibits tumor growth and induces systemic antitumor immunity. This mechanism has been validated in TNBC models (e.g., 4T1 breast cancer), where the combined strategy improves tumor suppression rates by over threefold and reduces lung metastasis. Nevertheless, hypoxia-induced metabolic reprogramming (e.g., ADSL-mediated fumarate accumulation) competitively inhibits cGAS activity, blocking STING signaling, while protective autophagy further weakens chemosensitivity by lysosomal degradation of STING protein. Future research should focus on exploring the specific mechanisms of the cGAS-STING pathway in different breast cancer subtypes, developing precise biomarkers and diagnostic tools, optimizing modulator development and application strategies, investigating multidisciplinary comprehensive treatment models, and identifying effective ways to overcome tumor heterogeneity and drug resistance. This will provide more precise and effective treatment options for breast cancer patients, improve their prognosis, and enhance survival rates and quality of life.