Nearly 20 million people are diagnosed with cancer each year with breast cancer being the most common among women. Triple negative breast cancer (TNBC), defined by its no/low expression of ER and PR and lack of amplification of HER2, makes up 15-20% of all breast cancer cases. While patients overall have a higher response to chemotherapy, this subgroup is associated with the lowest survival rate indicating significant clinical and molecular heterogeneity demanding alternate treatment options. Therefore, new therapies have been explored, with a large focus on utilizing the immune system. A whole host of immunotherapies have been studied including immune checkpoint inhibitors, now standard of care for eligible patients, and possibly the most exciting and promising is that of a TNBC vaccine. While currently there are no approved TNBC vaccines, this review highlights many promising studies and points to an antigen, p53, which we believe is highly relevant for TNBC.

Immunity has vital research value and promising applications in triple-negative breast cancer (TNBC). Nevertheless, few bibliometric analyses have systematically investigated this area. This study aimed to comprehensively review the collaboration and impact of countries, institutions, authors, and journals on the role of immunity in TNBC from a bibliometric perspective, evaluate the keyword co-occurrence of the knowledge structure, and identify hot trends and emerging topics. Articles and reviews related to immunity in TNBC were retrieved from the Web of Science core collection using subject search. A bibliometric study was conducted primarily using CiteSpace and VOSviewer. A total of 3,104 articles and reviews were included from January 1, 2014, through December 31, 2024. The number of articles on immunization in TNBC is rising. These publications are mainly from 415 institutions in 82 countries, led by China and the USA. Among these publications, Lajos Pusztai published the most papers, while Peter Schmid was co-cited the most. The most productive journals focused on molecular biology, biological immunology, and clinical medicine. Furthermore, co-citation analysis revealed that tumor microenvironment, biomarkers, and immune checkpoint inhibitors are current and developing research areas. The keywords "immunotherapy" and "nanoparticles" are also likely to be new trends and focal points for future research. This study adopted bibliometric and visualization methods to provide a comprehensive review of the research on immunization in TNBC. This article will help researchers better understand the dynamic evolution of the role of immunity in TNBC and identify areas for future research.

Over the recent decades the market potential of biologics has substantially expanded, and many of the top-selling drugs worldwide are now monoclonal antibodies or antibody-like molecules. The common gamma chain (γc) cytokines, Interleukin (IL-)2, IL-4, IL-7, IL-9, IL-15, and IL-21, play pivotal roles in regulating immune responses, from innate to adaptive immunity. Dysregulation of cell signaling by these cytokines is strongly associated with a range of immunological disorders, which includes cancer as well as autoimmune and inflammatory diseases. Given the essential role of γc cytokines in maintaining immune homeostasis, the development of therapeutic interventions targeting these molecules poses unique challenges. Here, we provide an overview of current biologics targeting either single or multiple γc cytokines or their respective receptor subunits across a spectrum of diseases, primarily focusing on antibodies, antibody-like constructs, and antibody-cytokine fusions. We summarize therapeutic biologics currently in clinical trials, highlighting how they may offer advantages over existing therapies and standard of care, and discuss recent advances in this field. Finally, we explore future directions and the potential of novel therapeutic intervention strategies targeting this cytokine family.

Nano-immunotherapy shows great promise in improving patient outcomes, as seen in advanced triple-negative breast cancer, but it does not cure the disease, with median survival under two years. Therefore, understanding resistance mechanisms and developing strategies to enhance its effectiveness in breast cancer is crucial. A key resistance mechanism is the pronounced desmoplasia in the tumor microenvironment, which leads to dysfunction of tumor blood vessels and thus, to hypoperfusion, limited drug delivery and hypoxia. Ultrasound sonopermeation and agents that normalize the tumor stroma have been employed separately to restore vascular abnormalities in tumors with some success. Here, we performed in vivo studies in two murine, orthotopic breast tumor models to explore if combination of ultrasound sonopermeation with a stroma normalization drug can synergistically improve tumor perfusion and enhance the efficacy of nano-immunotherapy. We found that the proposed combinatorial treatment can drastically reduce primary tumor growth and in many cases tumors were no longer measurable. Overall survival studies showed that all mice that received the combination treatment survived and rechallenge experiments revealed that the survivors obtained immunological memory. Employing ultrasound elastography and contrast enhanced ultrasound along with proteomics analysis, flow cytometry and immunofluorescene staining, we found the combinatorial treatment reduced tumor stiffness to normal levels, restoring tumor perfusion and oxygenation. Furthermore, it increased infiltration and activity of immune cells and altered the levels of immunosupportive chemokines. Finally, using machine learning analysis, we identified that tumor stiffness, CD8+ T cells and M2-type macrophages were strong predictors of treatment response.

Ferroptosis represents a distinctive and distinct form of regulated cellular death, which is driven by the accumulation of lipid peroxidation. It is distinguished by altered redox lipid metabolism and is linked to a spectrum of cellular activities, including cancer. In breast cancer (BC), with triple negative breast cancer (TNBC) being an iron-and lipid-rich tumor, inducing ferroptosis was thought to be a novel approach to killing breast tumor cells. However, in the recent past, a novel conceptual framework has emerged which posits that in addition to the promotion of tumor cell death, ferritin deposition has a potent immunosuppressive effect on the tumor immune microenvironment (TIME) via the influence on both innate and adaptive immune responses. TIME of BC includes various cell populations from both the innate and adaptive immune systems. In this review, the internal association between iron homeostasis and the progression of ferroptosis, along with the common inducers and protectors of ferroptosis in BC, are discussed in detail. Furthermore, a comprehensive analysis is conducted on the dual role of ferroptosis in immune cells and proto-oncogenic functions, along with an evaluation of the potential applications of immunogenic cell death-targeted immunotherapy in TIME of BC. It is anticipated that our review will inform future research endeavors that seek to integrate ferroptosis and immunotherapy in the management of BC.

Triple-negative breast cancer (TNBC) represents an aggressive subtype of breast cancer with limited therapeutic options. Motor neuron and pancreas homeobox 1 (MNX1) has been implicated in tumor progression, yet its roles in TNBC immune evasion remain unexplored. In the present study, we analyzed TCGA datasets and performed immunohistochemistry to evaluate MNX1 expression in TNBC tissues. DNA Affinity Purification and sequencing (DAP-seq) were used to identify MNX1 binding motifs. The regulatory relationship between MNX1 and CD24 was validated through dual luciferase reporter assays and expression manipulation in TNBC cell lines. Macrophage-mediated phagocytosis was assessed using in vitro co-culture systems and a humanized macrophage immune reconstruction mouse xenograft model. We found MNX1 expression was significantly elevated in TNBC tissues and correlated with poor patient prognosis. MNX1-knockdown significantly inhibited MDA-MB-468 cell proliferation in vitro and xenograft growth in vivo. In MDA-MB-231 cell, MNX1-overexpression promoted cell proliferation in vitro. We identified "TAATTA" as the MNX1 binding motif and demonstrated that MNX1 directly activates CD24 transcription. MNX1 knockdown in MDA-MB-468 cells enhanced macrophage phagocytosis, while its overexpression in MDA-MB-231 cells reduced phagocytosis. In the humanized mouse model, MNX1 downregulation increased macrophage infiltration and suppressed tumor growth. In summary, our findings reveal that MNX1 promotes TNBC immune evasion through transcriptional regulation of CD24. SIGNIFICANCE: We showed that CD24 is a novel target of transcription factor MNX1. MNX1-driven CD24-overexpression enables TNBC cells to evade from phagocytosis in both co-culturing TNBC cells with macrophage and in humanized macrophage immune reconstruction mouse xenograft model.

Cigarette smoking is a significant risk factor for cancer development with complex mechanisms. This study aims to investigate the impact of nicotine exposure on the regulation of stemness- and metastasis-related properties via cholinergic receptor nicotinic alpha 9 subunit (CHRNA9) and insulin-like growth factor-1 receptor (IGF1R) and to evaluate their therapeutic potential in triple-negative breast cancer (TNBC). We performed Kaplan-Meier survival analysis of public databases and revealed that high expression of CHRNA9, IGF1R signaling molecules, and stemness genes was significantly associated with poor recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in TNBC samples. Additionally, we examined two patient cohorts to determine the clinical associations between the expression levels of different genes (n = 67) and proteins (n = 42) and showed a strong positive correlation between the expression levels of CHRNA9, IGF1R signaling molecules, and stemness markers POU5F1/NANOG in tumor tissues. We carried out nicotine treatment and knockdown of CHRNA9 and IGF1R in TNBC cells to identify the effects on stemness-related properties in vitro. Furthermore, primary and secondary metastatic in vivo animal models were examined using micro-computed tomography (μCT) screening and in situ hybridization with a human Alu probe to detect tumor cells. Nicotine was found to upregulate the expression of CHRNA9, POU5F1, and IGF1R, influencing stemness- and metastasis-related properties. Knockdown of CHRNA9 expression attenuated nicotine-induced stemness-related properties in a TNBC cell model. Furthermore, knockdown of IGF1R expression significantly alleviated nicotine/CHRNA9-induced stemness features and cancer cell metastasis in cell cultures and lung metastatic mouse models. These results demonstrate that nicotine triggers IGF1R signaling, thereby enhancing stemness-related properties, cell migration, invasion, and tumor metastasis, resulting in a poorer prognosis for patients with TNBC. These findings highlight IGF1R as a promising therapeutic target for reducing stemness and metastasis in TNBC patients exposed to environmental nicotine. © 2025 The Pathological Society of Great Britain and Ireland.

Combination therapy has emerged as a leading trend in cancer treatment, having had a significant impact on the management of advanced-stage breast cancer. This approach, which relies on immune checkpoint modulation, has revolutionized the therapeutic landscape. However, the precise mechanisms underlying its therapeutic effects remain unclear.

Previously, we designed a bispecific antibody (BsAb) targeting PD-L1 (programmed cell death ligand 1) and the T cell immune checkpoint, LAG-3 (lymphocyte activation gene-3). In the present study, we evaluated the combination treatment of the BsAb (named Ba-PL) with doxorubicin (DOX) in a tumor-bearing mouse model and comprehensively investigated the underlying mechanisms involved.

The animal experiments demonstrated that the Ba-PL exerted an anti-tumor effect. Notably, mice treated with a combination of Ba-PL and DOX exhibited superior antitumor responses, mediated by the induction of robust immune cytokine responses. Furthermore, our findings revealed that this combination therapy restored depleted T cell activity and reinstated immune surveillance against tumors by reducing regulatory T cell levels. This immunotherapy combination exhibited favorable safety profiles and effectively prolonged the survival of tumor-bearing mice.

Blocking PD-L1 and LAG-3 in combination with doxorubicin is therapeutic potential approach for breast cancer and offers hope for improved patient outcomes.

Breast cancer (BC), which is the most common tumor in women, has greatly endangered women's lives and health. Currently, patients with BC receive comprehensive treatments, including surgery, chemotherapy, radiotherapy, endocrine therapy, and targeted therapy. According to the latest research, the development of BC is closely related to the inflammatory immune response, and the immunogenicity of BC has steadily been recognized. As such, immunotherapy is one of the promising and anticipated forms of treatment for BC. The potential values of miRNA in the diagnosis and prognosis of BC have been established, and aberrant expression of associated miRNA can either facilitate or inhibit progression of BC. In the tumor immune microenvironment (TME), miRNAs are considered to be an essential molecular mechanism by which tumor cells interact with immunocytes and immunologic factors. Aberrant expression of miRNAs results in reprogramming of tumor cells actively, which may suppress the generation and activation of immunocytes and immunologic factors, avoid tumor cells apoptosis, and ultimately result in uncontrolled proliferation and deterioration. Therefore, through activating and regulating the immunocytes related to tumors and associated immunologic factors, miRNA can contribute to the advancement of BC. In this review, we assessed the function of miRNA and associated immune system components in regulating the advancement of BC, as well as the potential and viability of using miRNA in immunotherapy for BC.

Breast cancer remains one of the most prevalent malignancies worldwide, underscoring an urgent need for innovative therapeutic strategies. Immunotherapy has emerged as a transformative frontier in this context. In triple-negative breast cancer (TNBC), the combination of immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors (ICIs) with chemotherapy has proven efficacious in both early and advanced clinical trials. These encouraging results have led to the approval of ICIs for TNBC, opening up new therapeutic avenues for challenging-to-treat patient populations. Furthermore, a multitude of ongoing trials are actively investigating the efficacy of immunotherapy-based combinations, including ICIs in conjunction with chemotherapy, targeted therapy and radiation therapy, as well as other novel strategies such as bispecific antibodies, CAR-T cells and cancer vaccines across all breast cancer subtypes, including HR-positive/HER2-negative and HER2-positive disease. This review provides a comprehensive overview of current immunotherapeutic approaches in breast cancer, highlighting pivotal findings from recent clinical trials and the potential impact of these advancements on patient outcomes.

DEK::AFF2 fusion-associated carcinoma, a recently recognized entity predominantly localized to the sinonasal tract and skull base, remains diagnostically challenging due to its poorly defined clinicopathological spectrum and epidemiological profile. Despite its deceptively bland histomorphology, this neoplasm is paradoxically linked to aggressive clinical behavior and elevated mortality rates.

To delineate the clinicopathological and molecular characteristics of DEK::AFF2 fusion-associated carcinomas to elucidate their biological drivers and refine therapeutic strategies.

A retrospective cohort study was conducted on some cases initially diagnosed as sinonasal papilloma of various types, with or without dysplasia or associated malignant transformation. DEK::AFF2 fusion was confirmed by DEK break-apart fluorescence in situ hybridization (FISH). Molecular features were assessed using immunohistochemistry (IHC) and in situ hybridization (ISH) to differential diagnosis. Clinical outcomes were analyzed for recurrence and disease-specific mortality.

Nine cases with DEK gene rearrangements were identified. The cohort comprised patients aged 51-76 years (median: 59 years), with a male predominance (M:F = 7:2). All cases demonstrated nuclear positivity for p40/p63 and AFF2 (30% ~90% tumor cells), while staining for p16 and Epstein-Barr encoded mRNA (EBER) was uniformly negative by IHC and ISH. Ki-67 index ranges from 5 to 40% with the median at 20%. Local recurrences occurred in 55.6% (5/9) of patients within 10-30 months following initial therapeutic intervention. The disease-specific mortality observed in 22.2% (2/9) of cases.

DEK::AFF2 fusion-associated carcinoma is characterized by a clinicopathological dichotomy: bland histological features contrast with aggressive biological behavior and poor prognosis in the nasal cavity, paranasal sinuses, and skull base.

Given the scarcity of effective therapeutic targets, metastatic triple negative breast cancer (mTNBC) has shorter survival times compared to other advanced breast cancer subtypes. Although chemo-immunotherapy with immune checkpoint inhibitors (ICIs) in PD-L1+ mTNBC has shown promise, survival benefit remains modest. Therefore, it is crucial to gain improved insight into the mechanisms underlying response and resistance to checkpoint inhibition in mTNBC.

We employed single cell RNA sequencing (scRNAseq), single cell secretomics, and flow cytometry to identify transcriptomic and proteomic peripheral immune cell signatures associated with response and non-response to anti-PD-1/PD-L1 therapy and chemotherapy in mTNBC.

Transcriptomic analysis reveal divergent transcriptional programming of CD33+ myeloid cells between responders and non-responders, even in pretreatment PBMC samples. This divergence, in responders, is characterized by an immune-promoting CD33+ cell phenotype involving IL1b signaling compared to non-responders, where an immunosuppressive phenotype marked by IL1b inhibition is observed. These baseline differences become more pronounced during the course of chemo-immunotherapy. Differences in CD33+ cell phenotype result in functional differences in lymphocyte activities between responders and non-responders. Depletion of CD33+ cells in pre-treatment samples from non-responders, restores T cell effector function.

Our findings highlight CD33+ cell phenotype as a key determinant of response to chemo-immunotherapy, which can be assessed from peripheral blood. This offers a valuable tool in the context of metastatic TNBC, in which tissue sampling is often challenging.

Immunotherapy has emerged as a promising treatment for metastatic triple-negative breast cancer (mTNBC), yet factors influencing its adoption remain unclear. This study examines clinical, sociodemographic, and facility-related determinants of immunotherapy use in mTNBC patients using the National Cancer Database (NCDB).

We conducted a retrospective cohort study of mTNBC patients from the NCDB (2015-2020), categorizing them into immunotherapy recipients and non-recipients. Patients with missing data on key variables were excluded. Univariable and multivariable logistic regression identified factors influencing immunotherapy adoption. Cox proportional hazards regression and log-rank tests assessed overall survival.

Among 1,887 mTNBC patients, 232 (12.2%) received immunotherapy. Factors positively associated with immunotherapy use included later diagnosis year (2018-2020: OR 5.35, p < 0.001), academic facilities (OR 1.43, p = 0.044), and private insurance (OR 1.34, p < 0.001). Lower likelihood of immunotherapy use was observed in older age (71+: OR 0.49, p = 0.019), rural facilities (OR 0.43, p = 0.042), Black race (OR 0.73, p = 0.039), Hispanic ethnicity (OR 0.53, p = 0.026), and higher Charlson comorbidity scores (≥ 2: OR 0.31, p = 0.035). Immunotherapy was associated with significantly improved survival (median 2.21 vs. 1.01 years, log-rank p < 0.001) and reduced mortality risk (HR 0.59, p < 0.001).

Immunotherapy use in mTNBC has increased in recent years, with clinical, sociodemographic, and facility-related factors influencing its adoption. Our findings highlight the importance of addressing disparities in access to immunotherapy to ensure equitable treatment and better survival outcomes for all mTNBC patients.

The comparative efficacy and safety of programmed death-ligand 1 (PD-L1) inhibitors versus programmed death protein 1 (PD-1) inhibitors in breast cancer treatment remain inconclusive, as no head-to-head randomized controlled trials (RCTs) conducted. This study aims to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors as monotherapy or in combination with chemotherapy for breast cancer. A systematic review and meta-analysis were performed using major databases and oncology conference proceedings. The primary outcomes were overall survival (OS) for advanced breast cancer and pathological complete response (PCR) rate for early breast cancer. Secondary outcomes included progression-free survival (PFS) for advanced breast cancer and incidence of adverse events (AEs). Seventeen studies met the inclusion criteria, consisting of seven RCTs on early-stage and 10 on advanced breast cancer. For advanced breast cancer, PD-1/PD-L1 inhibitors modestly improved OS compared to chemotherapy, with no significant differences between PD-1 and PD-L1 inhibitors. PD-L1 inhibitors showed greater improvement in PFS compared to PD-1 inhibitors. The likelihood of AEs of any grade was higher with PD-L1 inhibitor treatment than with PD-1 inhibitor treatment. In early breast cancer, combining PD-1/PD-L1 inhibitors with chemotherapy inducing higher PCR rates than chemotherapy alone, with PD-1 inhibitors achieving better outcomes than PD-L1 inhibitors. PD-1 inhibitors were linked to slightly higher rates of grade >2 AEs compared to PD-L1 inhibitors. The findings indicate that PD-1 inhibitors may offer advantages for advanced breast cancer due to similar OS and a lower rate of AEs. For early breast cancer, PD-1 inhibitors are recommended given their superior PCR rates.

Breast cancer remains one of the leading causes of cancer-related death, with triple-negative breast cancer (TNBC) accounting for 15-20% of cases. TNBC, characterized by the absence of ER, PR, and HER2 protein, is an aggressive form of breast cancer that is unresponsive to hormonal therapies and HER2-targeted treatments, with fewer treatment options and poorer prognosis. Oncolytic adenoviruses (Ad) are a potential treatment option for TNBC but require coxsackievirus and adenovirus receptors (CAR) to effectively enter and transduce cancer cells. This study investigates a novel neoadjuvant therapy to improve the efficacy of an oncolytic Ad with human telomerase reverse transcriptase (Ad-hTERT) in CAR-low TNBC tumors using folate surface-modified liposomes to enhance delivery. This therapy helps deescalate treatment by reducing or eliminating the need for checkpoint inhibitors or toxic chemotherapy combinations. In vitro studies using CAR-low TNBC murine 4T1-eGFP cells, CAR-high TNBC human MDA-MB-231-GFP cells and several other TNBC human cancer cell lines with varying CAR expression demonstrated significantly higher cytotoxicity with encapsulated Ad-hTERT compared to Ad-hTERT. Similar results were observed in patient-derived primary TNBC cells. In vivo studies in immunocompetent mice with CAR-low 4T1-eGFP tumors revealed that encapsulated Ad-hTERT, administered as neoadjuvant therapy, resulted in stable or reduced tumor sizes, improved survival rates, higher apoptosis of cancer cells, lower cancer cell proliferation, and increased T-cell infiltration in resected tumors. Furthermore, encapsulated Ad-hTERT prevented lung metastasis and tumor recurrence at the primary site, resulting in higher survival rates in mice. Thus, liposomal encapsulation of Ad may be a viable strategy for treating TNBC.

In the phase II NIMBUS trial, patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) and high tumor mutational burden (TMB ≥ 9 mut/Mb) received nivolumab (3 mg/kg biweekly) and low-dose ipilimumab (1 mg/kg every 6 weeks) for 2 years or until progression. The primary endpoint was objective response rate (ORR) per RECIST 1.1 criteria. Among 30 patients enrolled, the median TMB was 10.9 mut/Mb (range: 9-110) and the confirmed objective response rate was 20%. Secondary endpoints included progression-free survival, overall survival, clinical benefit rate, and safety and tolerability, including immune-related adverse events (irAEs). A prespecified correlative outcome was to evaluate the ORR in patients with a TMB ≥ 14 mut/Mb. Patients with TMB ≥ 14 mut/Mb (n = 6) experienced higher response rates (60% vs 12%; p = 0.041) and showed a trend towards improved progression-free survival and overall survival compared to patients with TMB < 14 mut/Mb. Exploratory genomic analyses suggested that ESR1 and PTEN mutations may be associated with poor response, while clinical benefit was associated with a decrease or no change in tumor fraction by serial circulating tumor DNA during treatment. Stool microbiome analysis revealed that baseline blood TMB, PD-L1 positivity, and immune-related diarrhea are associated with distinct taxonomic profiles. In summary, some patients with hypermutated HER2-negative MBC experience extended clinical benefit with a dual immunotherapy regimen; a higher TMB, and additional genomic and microbiome biomarkers may optimize patient selection for therapy with nivolumab plus low-dose ipilimumab. (Funded by Bristol Myers Squibb; ClinicalTrials.gov identifier, NCT03789110).

Inflammatory breast cancer (IBC) presents a formidable challenge due to its rapid progression and unique clinical characteristics within the various manifestations of breast cancer. Despite being rare, its aggressive nature demands innovative approaches beyond conventional treatments. Nanomedicine offers exciting possibilities for improving all types of breast cancer therapeutics including IBC. In this review, we critically assess the current treatment landscape for IBC, highlighting the limitations of traditional methods and addressing the pressing need for new therapeutic strategies. Although many nanomaterials have been explored for breast cancer therapeutics, either alone or in combination with other therapies, only a limited number of nanotherapeutics have been extensively studied for IBC treatment. This review further explores how advancements in nanotechnology, such as nanoparticle- mediated photothermal therapy, Photodynamic therapy, and nanomedicinal targeted therapies can offer novel avenues for addressing the unique biological, technological, and regulatory challenges posed by IBC. IBC-related various nanomedicines based combinatorial therapies are highlighted in this review. It also provides a forward-looking perspective on key research directions and clinical applications.

The PD-L1/PD-1 pathway is crucial for immune regulation and has become a target in cancer immunotherapy. However, in order to improve patient selection for immune checkpoint blockade (ICB) therapies, better selection criteria are needed. This study explores how the N-glycosylation of PD-L1 affects its interaction with PD-1 and ICB efficacy, focusing on its four N-linked glycosylation sites: N35, N192, N200, and N219.

Human PD-L1 glycosylation mutants-at each individual site or at all four sites together (Nx4)-were tested for their functional interaction with PD-1 using an artificial immune checkpoint reporter assay (IcAR-PD1). The blocking efficacy of anti-PD-L1 and anti-PD-1 antibodies was evaluated using human breast cancer cell lines (MDA-MB231 and MCF7), as well as A375 melanoma and A549 lung carcinoma cells expressing the glycosylation mutants. Results were validated through ex vivo activation and cytotoxicity assays using human CD8+ T cells.

The binding of the PD-L1N35A mutant to PD-1 was not effectively blocked by anti-PD-L1 and anti-PD-1 ICBs. In contrast, high blocking efficacy of PD-L1 binding to PD-1 was obtained at minimal ICB concentrations when PD-L1 did not express any glycosylation site (PD-L1Nx4 mutant). The PD-L1N35A mutant produced elevated levels of PD-L1 as a soluble (sPD-L1) and extracellular vesicles (EV)-bound molecule; in contrast, the PD-L1Nx4 mutant had lower sPD-L1 and EV levels. PD-L1 glycosylation status influenced the ability of PD-L1 interactions with PD-1 to down-regulate T-cell activation and cytotoxicity, with the PD-L1N35A mutant showing the lowest levels of T cell functions and the PD-L1Nx4 mutant the highest.

The N-glycosylation of PD-L1 at all four sites interferes with the ability of anti-PD-L1 and anti-PD-1 ICBs to block PD-L1 interactions with PD-1; in contrast, glycosylation at the N35 site enhances ICB blocking efficacy. These effects are connected to the ability of sPD-L1 to compete with ICB binding to PD-L1 or PD-1. Thus, assessing PD-L1 glycosylation, beyond expression levels, could improve patient stratification and outcomes.

The Phase 2 IMPRIME 1 study evaluated the combination of the pathogen-associated molecular pattern (PAMP) Imprime with the immune checkpoint inhibitor (ICI) pembrolizumab as second or later line of treatment (2 L+) for patients with metastatic triple-negative breast cancer (mTNBC). Eligible patients with mTNBC received weekly Imprime (4 mg/kg) intravenously in combination with pembrolizumab (200 mg every 3 weeks). Primary endpoints were overall response rate (ORR) and safety. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression free survival (PFS), and overall survival (OS). Exploratory endpoints included correlations between immune cell activation markers in tumor tissues and blood and response to therapy. Of the 42 evaluable patients, six had a response (one complete, five partial), with an ORR of 14.3% by RECIST v1.1. Median PFS was 2.7 months, median OS was 16.4 months, and DCR was 54.8%, with responders achieving a median DoR of 15.2 months. Therapy was generally well tolerated and resulted in an increase of immune activation markers, with higher levels of activation in peripheral blood associated with response and improved survival. The combination of Imprime and pembrolizumab was safe and demonstrated immune activation in tumor tissues and peripheral blood in patients with TNBC. Improved response rates were observed compared to historical studies of ICI monotherapy in similar patient populations. Study number (ClinicalTrials.gov trial registration): NCT02981303.

Cancer immunotherapies have transformed oncology by utilizing the immune system to target malignancies; however, limitations in efficacy and potential side effects remain significant challenges. Nanoparticles have shown promise in enhancing drug delivery and improving immune activation, with the potential for numerous modifications to tailor them for specific environments or targets. Integrating nanoplatforms offers a promising avenue to overcome these hurdles, enhancing treatment outcomes and reducing adverse effects. By improving drug delivery, targeting, and immune modulation, nanoplatforms can unlock the full potential of cancer immunotherapy. This review explores the role of nanoplatforms in addressing these limitations and enhancing cancer immunotherapy outcomes, examining various types of nanoplatforms. Understanding the mechanisms of immunomodulation through nanoplatform deliveries is crucial. We discuss how these nanoplatforms interact with the tumor microenvironment, modulate tumor-associated macrophages and regulatory T cells, activate immune cells directly, enhance antigen presentation, and promote immunological memory. Further benefits include combination approaches integrating nanoplatforms with chemotherapy, radiotherapy, and phototherapy. Immunotherapy is a relatively new approach, but numerous clinical studies already utilize nanoplatform-based immunotherapies with promising results. This review aims to provide insights into the potential of nanoplatforms to enhance cancer immunotherapy and pave the way for more effective and personalized treatment strategies.

Breast cancer is the most frequently diagnosed cancer globally and the second leading cause of cancer-related deaths in American women. Triple-negative breast cancer (TNBC) lacks estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Thus, fewer targeting therapies are available for this most aggressive subtype. The A Disintegrin and Metalloproteinase (ADAM) family plays a vital role in cancer pathophysiology. Previous studies focused on single ADAM members. However, none of these have entered into the clinical arena as diagnostics or therapeutics for breast cancer. In this study, we demonstrate the upregulation of a panel of ADAM members in TNBC, and overexpression of all the individual ADAMs tested are correlated with poor patient survival, making it unlikely that targeting a single ADAM member would be effective. Reverse-phase protein array and multiplexed immunofluorescence revealed that ADAM10/15/17 expression was associated with activated mTOR signaling. Individual knockdown of ADAM10, ADAM15, or ADAM17 modestly reduced mTOR signaling, cellular proliferation and survival. However, the concurrent knockdown of the three ADAMs drastically decreased mTOR signaling and cellular aggressiveness. Consistently, combined targeting of ADAMs and mTOR increased inhibitory efficacy compared to monotherapy in ADAM-mTOR-activated tumor growth and invasion in vitro and in immunodeficient and immunocompetent mice. These results establish a functional link between ADAMs and activation of mTOR signaling, suggesting the ADAM-mTOR axis as a therapeutic target and biomarker for ADAM-enriched TNBC and, potentially, other tumor lineages with high ADAM activity.

Pembrolizumab has been approved for the immunotherapy of programmed death ligand 1 (PD-L1)-positive triple-negative breast cancer (TNBC) based on the KEYNOTE-355 trial. However, cost-effectiveness evidence is limited. The purpose of this study was to evaluate the cost-effectiveness of pembrolizumab plus chemotherapy compared with chemotherapy alone for patients with PD-L1-positive inoperable or metastatic TNBC from a Japanese healthcare perspective.

The cost-effectiveness analysis was performed for pembrolizumab, of which the drug price was determined at 214,498 Japanese yen (JPY), or 1631 US dollars (USD) (1 USD = 131.5 JPY) for KEYTRUDA® (100 mg), using a partition survival model based on the KEYNOTE-355 trial subgroup analysis in Japan. The comparison was made using quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER). One-way deterministic and probabilistic sensitivity analyses (PSA), which evaluate the impact of parameter uncertainty, were performed to assess the robustness and calculate the acceptable probability, defined as the probability of the ICER being below the willingness-to-pay (WTP).

Pembrolizumab plus chemotherapy provided an additional 0.676 QALYs at an incremental cost of 8,503,072 JPY. The ICER for pembrolizumab plus chemotherapy compared with conventional chemotherapy was 12,577,178 JPY (95,644 USD) per QALY. The ICER per QALY was below the willingness-to-pay threshold of 15,000,000 JPY. PSAs revealed that the acceptable probability was 83.9% at 15,000,000 JPY.

The pembrolizumab plus chemotherapy is likely to be a cost-effective option compared with conventional chemotherapy for patients with PD-L1-positive inoperable or metastatic TNBC in a Japanese medical environment from a healthcare system.

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous variant of breast cancer distinguished by a lack of targeted therapies, posing significant challenges in diagnosis and treatment. Metabolomics, the comprehensive study of small compounds in biological systems, has been identified as an instrument for revealing the metabolic underpinnings of TNBC. This review highlights recent advancements in metabolomic approaches, such as mass spectrometry and nuclear magnetic resonance, which have identified metabolic vulnerabilities, resistance mechanisms, and potential therapeutic targets. Key findings include alterations in fatty acid, amino acid, and glutathione metabolism, along with hypoxia-driven metabolic reprogramming that contributes to disease progression. The combination of metabolomics with multi-omics techniques, supported by advanced computational methods such as machine learning, offers a pathway to overcome challenges in data standardization and biological complexity. Emerging strategies, including the use of artificial intelligence and multidimensional omics approaches, are paving the way for personalized medicine by enabling the discovery of novel biomarkers and targeted therapies. Despite these advances, significant hurdles remain, including the need for robust data standardization, validation of findings in diverse patient cohorts, and seamless integration with clinical workflows. By addressing these challenges, metabolomics has the potential to revolutionize TNBC management, offering tools for early detection, precision therapy, and improved patient outcomes. This review underscores the importance of interdisciplinary collaboration to translate metabolomic insights into actionable clinical applications.

Immunotherapy targeting negative immune checkpoint regulators to enhance the anti-tumour immune response holds promise in the treatment of TNBC. V-domain Ig suppressor of T-cell activation (VISTA) is an immune checkpoint molecule, known to be upregulated and involved in modulating tumour immunity in TNBC. However, how VISTA affects immune response and its therapeutic potential in TNBC remains unclear.

Here, we examined VISTA expression and cellular distribution in TNBC patients' samples and pre-clinical TNBC mouse model. Functional assays were performed to assess the impact of VISTA blockade on macrophage phenotypes, CD8 + T cell infiltration and activation, and overall anti-tumour immune response.

In this study we show that VISTA expression levels are increased in TNBC patients' samples and pre-clinical mouse models compared to non-involved breast tissue and VISTA is mainly expressed on tumour infiltrating macrophages and neutrophils. Blocking VISTA reverts macrophages immunosuppressive phenotypes, increases CD8 + T cell infiltration and activation, and enhances an anti-tumour immune response. Mechanistically, we show that neutralising VISTA on macrophages enhances their immune-stimulatory functions and inhibits the suppressive effect of macrophages on CD8 + T cells activation.

These findings provide the rationale for the development of anti-VISTA targeting strategies in the treatment of TNBC.

The molecular and cellular pathways through which breast cancer evades immunosurveillance remain poorly understood. Recent data from Camargo et al. demonstrate that - on recruitment to the tumor microenvironment by ductal macrophages - a heterogeneous population of neutrophils can establish physical contacts with malignant cells within spatial niches that sustain mammary oncogenesis.

Breast cancer is the most prevalent cancer among women worldwide, with various subtypes that require distinct treatment approaches. Among these, Triple-Negative Breast Bancer (TNBC) is recognized as the most aggressive form, often associated with poor prognosis due to its lack of targeted therapeutic options. This review specifically focuses on Radiotherapy (RT) as a treatment modality for TNBC, evaluating recent advancements and ongoing challenges, particularly the issue of radioresistance. RT remains an essential part in the management of breast cancer, including TNBC. Over the years, multiple improvements have been made to enhance RT effectiveness and minimize resistance. The introduction of advanced techniques such as Stereotactic Body Radiation Therapy (SBRT) and Stereotactic Radiosurgery (SRS) has significantly improved precision and reduced toxicity. More recently, proton radiation therapy, a novel RT modality, has been introduced, offering enhanced dose distribution and reducing damage to surrounding healthy tissues. Despite these technological advancements, a subset of TNBC patients continues to exhibit resistance to RT, leading to recurrence and poor treatment outcomes. To overcome radioresistance, there is an increasing interest in combining RT with targeted therapeutic agents that sensitize cancer cells to radiation. Radiosensitizing drugs have been explored to enhance the efficacy of RT by making cancer cells more susceptible to radiation-induced damage. Potential candidates include DNA damage repair inhibitors, immune checkpoint inhibitors, and small-molecule targeted therapies that interfere with key survival pathways in TNBC cells. In conclusion, while RT remains a crucial modality for TNBC treatment, radioresistance remains a significant challenge. Future research should focus on optimizing RT techniques while integrating radiosensitizing agents to improve treatment efficacy. By combining RT with targeted drug therapy, a more effective and personalized treatment approach can be developed, ultimately improving patient outcomes and reducing recurrence rates in TNBC.

Breast cancer remains a major global health challenge. While advances in precision oncology have contributed to improvements in patient outcomes and provided a deeper understanding of the biological mechanisms that drive the disease, historically, research and patients' allocation to treatment have heavily relied on single-omic approaches, analyzing individual molecular dimensions such as genomics, transcriptomics, or proteomics. While these have provided deep insights into breast cancer biology, they often fail to offer a complete understanding of the disease's complex molecular landscape.

In this review, the authors explore the recent advancements in multi-omic research in the realm of breast cancer and use clinical data to show how multi-omic integration can offer a more holistic understanding of the molecular alterations and their functional consequences underlying breast cancer.

The overall developments in multi-omic research and AI are expected to complement precision diagnostics through potentially refining prognostic models, and treatment selection. Overcoming challenges such as cost, data complexity, and lack of standardization is crucial for unlocking the full potential of multi-omics and AI in breast cancer patient care to enable the advancement of personalized treatments and improve patient outcomes.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options and poor prognosis. The gut microbiota, a diverse community of microorganisms in the gastrointestinal tract, plays a crucial role in regulating immune responses through the gut-immune axis. Recent studies have highlighted its significant impact on TNBC progression and the efficacy of immunotherapies. This review examines the interactions between gut microbiota and the immune system in TNBC, focusing on key immune cells and pathways involved in tumor immunity. It also explores microbiota modulation strategies, including probiotics, prebiotics, dietary interventions, and fecal microbiota transplantation, as potential methods to enhance immunotherapeutic outcomes. Understanding these mechanisms offers promising avenues for improving treatment efficacy and patient prognosis in TNBC.

Triple-negative breast cancer (TNBC), accounting for about 10%-20% of all breast cancer cases, is characterized by its aggressive nature, high recurrence rates, and poor prognosis. Unlike other breast cancer subtypes, TNBC lacks hormone receptors and specific molecular targets, limiting therapeutic options. In recent years, immune checkpoint inhibitors (ICIs) have shown promise in treating TNBC by targeting immune evasion mechanisms. Despite these advancements, several issues remain unresolved, including low response rates in programmed cell death ligand 1 (PD-L1) negative TNBC subtypes and the challenge of predicting which patients will benefit from ICIs. Consequently, there is growing interest in identifying reliable biomarkers beyond PD-L1 expression. This review synthesizes recent studies to provide a comprehensive perspective on ICI therapy in TNBC, clarifying the status of single-agent ICI therapies and combination strategies, emphasizing the need for further research into biomarkers. These insights provide clues for more personalized and effective treatment approaches, ultimately aiming to improve clinical outcomes for patients with TNBC.

Triple-negative breast cancer (TNBC) is one of the most heterogeneous and menacing forms of breast cancer, with no sustainable cure available in the current treatment landscape. Its lack of targets makes it highly unresponsive to various treatment modalities, which is why chemotherapy continues to be the primary form of treatment, despite the high rates of patients developing chemoresistance. In recent years, however, there has been significant progress in identifying and understanding the role of several aspects that might contribute to genomic instability and other hallmarks of cancer, including cellular proteins, immune targets, and epigenetic mechanisms, which are desirable as they permit reversibility easier than the often-adamant genetic changes.

A literature review was conducted on the role of various TNBC associated biomarkers, their therapeutic applications, and their role in tumorigenesis and tumor maintenance, with a focus on linking both the driving biological mechanisms and emerging treatment options for TNBC.

Shifting the focus of treatment to identify crucial tumor cell subpopulations and associated biomarkers, such as local immune cell populations and cancer stem cells, could potentially solve or simplify decades' worth of problems that are associated with TNBC, bolstering early detection and the evolution of precision medicine and treatment. The techniques that can be used here are epigenetic analysis and RNA sequencing. Biomarkers, such as PD-L1, survivin, and ABC transporters, are implicated in several crucial processes that maintain tumors, such as cell proliferation, metastasis, immunosuppression, and stemness. Complex treatment options such as, immunotherapy, pathway inhibition, PARP inhibition, virotherapy, and RNA targeting have been considered for TNBC. Phytochemicals are also being considered as a treatment modality for TNBC, as a supplement to chemotherapy and radiation therapy, or as sole treatment.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that typically lacks effective targeted therapies, leading to limited treatment options. Chemotherapy remains the primary treatment modality; however, in recent years, new immunotherapy approaches, such as immune checkpoint inhibitors, have shown positive results in some patients. Although the development of TNBC is closely associated with BRCA gene mutations, the tumor immune microenvironment (TIME) plays a crucial role in tumor progression and immune escape. Tumor angiogenesis, the accumulation of immunosuppressive cells, and alterations in immune molecules collectively shape an environment unfavorable for anti-tumor immune responses. Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) promote immune escape by secreting immunosuppressive factors. Therefore, combination strategies of anti-angiogenic and immune checkpoint inhibitory therapies have shown synergistic effects in clinical trials, while new targeted therapies such as TGF-β inhibitors and IL-1β inhibitors offer new options for TNBC treatment. With the development of personalized medicine, combining immunotherapy and targeted therapies brings new hope for TNBC patients.

This study was aimed to elucidate the cytotoxic effects of γδT cells on triple-negative breast cancer (TNBC) cells and assess their antitumor efficacy in a mouse xenograft model. Furthermore, the underlying mechanisms of γδT cell action on TNBC were explored. The study utilized three TNBC cell lines (MDA-MB-231, MDA-MB-468, and BT-549) as target cells, with γδT cells serving as effector cells. Cytotoxicity was assessed in different effector-to-target ratios (E:T) at 5:1, 10:1, and 20:1 subsequent to coculture. To evaluate the antitumor effects of γδT cells in vivo, a xenograft mice model was established by inoculating MDA-MB-231 cells into the mammary fat pad of B-NDG mice. The mice received tail vein injections of γδT cells at different doses. The effects on tumor growth, mouse body weight, and γδT cell accumulation in the spleen were then determined. γδΤ cells at E:T of 10:1 exhibited significant cytotoxicity against all three TNBC cell lines, indicating a statistically significant difference compared to the control group (p < 0.0001). The cytotoxic effect at this ratio was superior to that at 20:1 and 5:1 effector-to-target ratios, as evidenced by statistical significance (p < 0.05). Following 21 days of adoptive transfer via tail vein injection, γδΤ cells at both low and high doses significantly reduced tumor volume and mass compared to the PBS control group (p < 0.001). This reduction was accompanied by an increased accumulation of γδΤ cells in the spleen. In conclusion, γδΤ cells exert significant cytotoxic effects on TNBC cells and effectively inhibit the growth of breast cancer xenografts in mice while also promoting the accumulation of γδΤ cells in the mouse spleen.

We hypothesized treatment with nivolumab and stereotactic radiosurgery (SRS) would be feasible, well tolerated, and may improve intracranial tumor control over SRS alone for breast cancer brain metastases (BCBM).

The study is a phase Ib trial of nivolumab and SRS for BCBM.

NCT03807765. Key eligibility criteria include BCBM of all subtypes, age ≥18, Eastern Cooperative Oncology Group Performace Status (ECOG-PS)≤2 with ≤10 brain metastases. Treatment was initiated with a dose of nivolumab (480 mg intravenously) that was repeated every 4 weeks. The initial dose of nivolumab was followed 1 week later by SRS. Blood was collected at baseline and every 4 weeks for flow cytometry and cell-free DNA (cfDNA) assessment.

A total of 12 patients received SRS to 17 brain metastases. Breast cancer subtypes included triple negative (50%), hormone receptor (HR)+/HER2- (33%), and HR-/HER2+ (17%). Median follow-up from start of protocol therapy is 56 months. No cases of radionecrosis were noted. Two lesions were noted to undergo local failure, both pathologically confirmed, for a 12-month local control of 94%. Median distant intracranial control was 7.4 months with a 12-month control rate of 33%. Median systemic progression-free survival was 7.7 months with a 12-month rate of 42%. Median overall survival (OS) was 24.7 months with a 12-month OS of 75%. Most patients were noted to have an increase in cfDNA throughout study treatment, at week 5 compared with baseline (83%), week 25 compared with baseline (89%), and 100% at first follow-up. Intracranial control was associated with lower levels of CD4 regulatory T cells (Treg) (p=0.03) and higher levels of CD4 T effector memory (p=0.04).

Nivolumab and SRS is a safe and feasible treatment option in BCBM. Long-term follow-up revealed no cases of radiation necrosis.

NCT03807765.

This review discusses reprogramming the breast tumor immune microenvironment from an immunosuppressive cold state to an immunologically active hot state. A complex interplay is revealed, in which the accumulation of metabolic byproducts-such as lactate, reactive oxygen species (ROS), and ammonia-is shown to impair T-cell function and promote tumor immune escape. It is demonstrated that the tumor microenvironment (TME) is dominated by immunosuppressive cytokines, including interleukin-10 (IL-10), transforming growth factorβ (TGFβ), and IL-35. Notably, IL-35 is produced by regulatory T cells and breast cancer cells. The conversion of conventional T cells into IL-35-producing induced regulatory T cells, along with the inhibition of pro-inflammatory cytokine secretion, contributes to the suppression of anti-tumor immunity. It is further demonstrated that key immune checkpoint molecules-such as PD-1, PDL1, CTLA-4, TIM-3, LAG-3, and TIGIT-are upregulated within the TME, leading to Tcell exhaustion and diminished immune responses. The blockade of these checkpoints is shown to restore T-cell functionality and is proposed as a strategy to convert cold tumors into hot ones with robust effector cell infiltration. The therapeutic potential of chimeric antigen receptor (CAR)T cell therapy is also explored, and targeting specific tumor-associated antigens, such as glycoproteins and receptor tyrosine kinases, is highlighted. It is suggested that CART cell efficacy can be enhanced by combining these cells with immune checkpoint inhibitors and other immunomodulatory agents, thereby overcoming the barriers imposed by the immunosuppressive TME. Moreover, the role of the microbiome in regulating estrogen metabolism and systemic inflammation is reviewed. Alterations in the gut microbiota are shown to affect the TME, and microbiome-based interventions are proposed as an additional means to facilitate the cold-to-hot transition. It is concluded that by targeting the metabolic and immunological pathways that underpin immune suppression-through combination strategies involving checkpoint blockade, CART cell therapies, and microbiome modulation-the conversion of the breast TME from cold to hot can be achieved. This reprogramming is anticipated to enhance immune cell infiltration and function, thereby improving the overall efficacy of immunotherapies and leading to better clinical outcomes for breast cancer patients.

Breast cancer (BC) is the second leading cause of death among women worldwide. Immunotherapy has become an effective treatment for BC patients due to the rapid development of medical technology. Considerable breakthroughs have been made in research, marking the beginning of a new era in cancer treatment. Among them, various cancer immunotherapies such as immune checkpoint inhibitors (ICIs), cancer vaccines, and adoptive cell transfer are effective and have good prospects. The tumor microenvironment (TME) plays a crucial role in determining the outcomes of tumor immunotherapy. Tumor-associated macrophages (TAMs) are a key component of the TME, with an immunomodulatory effect closely related to the immune evasion of tumor cells, thereby affecting malignant progression. TAMs also significantly affect the therapeutic effect of ICIs (such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors). TAMs are composed of multiple heterogeneous subpopulations, including M1 phenotypes macrophages (M1) and M2 phenotypes macrophages (M2). Furthermore, they mainly play an M2-like role and moderate a variety of harmful consequences such as angiogenesis, immunosuppression, and metastasis. Therefore, TAMs have become a key area of focus in the development of tumor therapies. However, several tumor immunotherapy studies demonstrated that ICIs are effective only in a small number of solid cancers, and tumor immunotherapy still faces relevant challenges in the treatment of solid tumors. This review explores the role of TAMs in BC immunotherapy, summarizing their involvement in BC development. It also explains the classification and functions of TAMs, outlines current tumor immunotherapy approaches and combination therapies, and discusses the challenges and potential strategies for TAMs in immuno-oncology treatments.

Triple-negative breast cancer (TNBC) is an aggressive subtype requiring further knowledge of biomarkers to improve targeted therapy. A major resistance mechanism involves breast cancer stem cells (BCSCs) evading the immune system. Neoadjuvant or adjuvant chemotherapy may alter BCSCs and the patients' immune response. We conducted a retrospective study including 29 early-stage TNBC patients resistant to chemotherapy diagnosed at the Catalan Institute of Oncology (Girona, Spain) in 2010-2019. We obtained 44 paired tumor samples (pre- and post-chemotherapy) from the Tumor Biobank, assessing BCSC biomarkers (CD44, CD24, and ALDH1), PD-L1, and percentages of stromal tumor-infiltrating lymphocytes (TILs). Clinicopathological characteristics were also collected. At baseline, 68% of tumors had high CD44 expression, 55% showed low CD24 expression, 9% had high ALDH1 expression, 91% were PD-L1-negative (<1%), and 64% had a low percentage of stromal TILs. PD-L1 expression significantly increased post-chemotherapy, with 50% of initially negative tumors becoming PD-L1 positive (≥1%) (p = 0.006). No significant changes were observed in BCSC markers or TILs. No association was found between baseline BCSCs and increased PD-L1 expression post-chemotherapy. At a median follow-up of 58.9 months, 48.3% of patients were alive, with non-significant favorable trends in time to progression, disease-free survival, and overall survival in the PD-L1 positivization cohort post-chemotherapy. In conclusion, high-risk early-stage TNBC tumors increased PD-L1 expression after chemotherapy, potentially affecting clinical outcomes. BCSCs remained stable and independent of the tumor immunogenicity post-chemotherapy. Further studies are needed to explore the relationship between BCSCs and the immunogenicity profile, for development of new combined therapeutic strategies.

Recent clinical trials have suggested that solid cancers with mismatch repair (MMR) deficiency are highly responsive to immunotherapy, regardless of cancer types. Previous MMR-related studies on breast cancer have predominantly focused on germline variants. However, the somatic MMR alterations have not been comprehensively characterized in breast cancer. In this study, we integrated genomic, transcriptomic, and clinical data from over 3000 breast cancer cases across six public cohorts. Our findings revealed that 1.2% of breast cancers harbored oncogenic somatic MMR alterations, with triple-negative breast cancer (TNBC) demonstrating the highest mutation rate at 3.1%. Additionally, somatic MMR alterations were significantly associated with microsatellite instability-high (MSI-H) and MMR-related mutational signatures, indicating that somatic MMR alterations led to impaired function of the MMR system. Biallelic inactivation of MMR genes resulted in a more pronounced loss of MMR function compared to monoallelic inactivation. Importantly, these MMR alterations significantly increased the tumor mutational burden (TMB) and neoantigen load in breast cancer, regardless of MSI-H status. These findings indicate that the frequency of MMR alterations is highest in TNBC and that MMR alterations in breast cancer can lead to MMR functional deficiencies, suggesting that some patients harboring such alterations may benefit from immunotherapy.

Standard of care (SoC) for patients with advanced triple-negative breast cancer (TNBC) whose tumors express PD-L1 (combined positive score ⩾ 10) is chemotherapy plus anti-PD-(L)1 inhibitors; however, prognosis and survival for most patients is poor. Datopotamab deruxtecan (Dato-DXd), a novel antibody-drug conjugate comprising a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to a potent topoisomerase I inhibitor payload via a plasma-stable, cleavable, tetrapeptide-based linker, has shown preliminary activity as mono or combination therapy in advanced/metastatic TNBC.

TROPION-Breast05 is an ongoing randomized, open-label, multicenter phase III study. The primary objective is to demonstrate the superiority of Dato-DXd in combination with durvalumab (an anti-PD-L1 antibody) versus SoC treatment in patients with PD-L1-high locally recurrent inoperable or metastatic TNBC.

Patients (⩾18 years) will be randomized 1:1 to receive Dato-DXd (6 mg/kg intravenously (IV) every 3 weeks (Q3W)) plus durvalumab (1120 mg IV Q3W) or investigator's choice of chemotherapy (ICC; paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin) plus pembrolizumab (200 mg IV Q3W). In selected countries, patients will also be randomized (1:1:1) to a third arm of Dato-DXd monotherapy. The primary study endpoint is progression-free survival (PFS) per blinded independent central review (Dato-DXd plus durvalumab arm vs ICC plus pembrolizumab arm). Overall survival is a key secondary endpoint; other secondary endpoints include PFS (investigator-assessed), objective response rate, duration of response, clinical benefit rate at Week 24 (all assessed in the Dato-DXd plus durvalumab arm vs ICC plus pembrolizumab arm), patient-reported outcomes, and safety.

The study is approved by independent ethics committees or institutional review boards at each study site. All patients will provide written informed consent.

TROPION-Breast05 will assess the potential role of Dato-DXd with or without durvalumab in patients with PD-L1-high advanced or metastatic TNBC. The findings of this trial could lead to a new treatment option for these patients.

ClinicalTrials.gov identifier: NCT06103864 (Date of registration: 27 October 2023).