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.

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.

We aimed to clarify the role of PD-L1 promoter methylation in bladder cancer by analyzing PD-L1 methylation and mRNA expression in FFPE samples, along with PD-L1 mRNA and protein levels in urine samples from bladder urothelial carcinoma patients. We analyzed PD-L1 promoter methylation in 43 bladder urothelial carcinoma tissue samples and 41 non-malignant bladder tissues using methylation-sensitive high-resolution melting analysis to assess two CpG islands (cg15837913, cg19724470). PD-L1 mRNA expression in tissues and urine samples, along with PD-L1 protein levels in urine, were evaluated. The bladder urothelial carcinoma group showed significantly higher methylation rates for cg19724470 and cg15837913 compared to controls (P = 0.016, P = 0.049 respectively). In the patient group, tissue PD-L1 mRNA expression was 15.22 times higher and urinary PD-L1 mRNA expression 6.56 times higher in the cg19724470 unmethylated group compared to the methylated group. Urinary PD-L1 protein concentration was twice as high in the cg19724470 unmethylated group compared to the methylated group. In the patients, tissue PD-L1 mRNA expression was 4.58 times higher and urinary PD-L1 mRNA expression 2.58 times higher in the cg15837913 unmethylated group compared to the methylated group. Moreover, the urinary PD-L1 protein concentration was 1.7 times higher in the cg15837913 unmethylated group than in the methylated group (P = 0.036). A positive correlation was observed between tissue PD-L1 mRNA and both urine PD-L1 mRNA and protein levels and between urine PD-L1 mRNA and protein levels. This study suggests that PD-L1 methylation may be a key epigenetic regulator influencing PD-L1 expression and disease pathogenesis in bladder urothelial carcinoma.

Immunotherapeutics against triple-negative breast cancer (TNBC) hold great promise. In this work, we provide a combination therapy for simultaneous increasing tumor immunogenicity and down-regulating programmed cell death ligand 1 (PD-L1) to boost antitumor immunity in TNBC. We prepare bis (diethyldithiocarbamate)-copper/indocyanine green nanoparticles (CuET/ICG NPs) simply in aqueous with one-pot method. CuET/ICG NPs interfere mitochondria, reduce oxygen consumption, and alleviate tumor hypoxia to potentiate photodynamic therapy (PDT) for amplifying immunogenic cell death (ICD). Meanwhile, mitochondria dysfunction leads to energy stress and activates AMPK pathway. As a result, CuET/ICG NPs downregulates membrane PD-L1 (mPD-L1) on both 4T1 cancer cells and cancer stem cells (CSCs) through AMP-activated protein kinase (AMPK)-mediated pathway in hypoxia. Cooperatively, the combinational therapy activates antitumor immunity and triggers long lasting immune memory response to resist tumor re-challenge. Our study represents an attempt that conquers tumor immunosuppressive microenvironment with simple biomedical materials and multimodality treatments.

Triple‑negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype of BC characterized by the absence of estrogen, progesterone and human EGFR2 receptors. This lack of receptors renders it unresponsive to standard targeted therapies. Despite advances made in understanding the molecular landscape of TNBC, its poor prognosis and high recurrence rates underscore the urgent need for innovative therapeutic approaches. This review explores the effects of key prognostic markers, such as Ki‑67, programmed cell death ligand 1, BRCA1/2 mutations, E‑cadherin loss and EGFR alterations. It also examines critical pathways, including the PI3K/AKT/mTOR and mutant p53 pathways, which are prerequisites for TNBC progression and therapy resistance, and discusses the therapeutic potential of directly targeting these key molecules and their associated signaling pathways. In addition, recent advances in targeted therapies were highlighted, such as immune checkpoint inhibitors, and the statuses of emerging strategies were presented, such as chimeric antigen receptor‑T cell therapy and small inhibitory RNA‑based treatments. Given the molecular heterogeneity of TNBC, the importance of precision medicine was also discussed and it was emphasized that this approach is becoming an increasingly critical aspect of personalized treatment strategies. Resistance to existing therapies presents a major challenge to the effective treatment of TNBC, and thus, the development of future therapeutic strategies requires technical innovations. By integrating these insights, this review aims to provide a comprehensive overview of current and future means of improving TNBC 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.

In pursuit of meeting the ever-rising demand for cancer therapies, cross-presentation-based glyconanovaccines (GNVs) targeting C-type lectin receptors (CLRs) on DCs have shown significant potential as cutting-edge cancer immunotherapy. GNVs are an attractive approach to induce anti-cancer cytotoxic T lymphocyte responses. Despite immune checkpoints (ICs) being well established and an obstacle to the success of GNVs, glycan-lectin circuits are emerging as unique checkpoints due to their immunomodulatory functions. Given the role of aberrant tumor glycosylation in promoting immune evasion, mitigating these effects is crucial for the efficacy of GNVs. Lectins, such as siglecs and galectins, are detrimental to the tumor immune landscape as they promote an immunosuppressive TME. From this perspective, this review aims to explore glycan-lectin ICs and their influence on the efficacy of GNVs. We aim to discuss various ICs in the TME followed by drawbacks of immune checkpoint inhibitors (ICIs). We will also emphasize the altered glycosylation profile of tumors, addressing their immunosuppressive nature along with ways in which CLRs, siglecs, and galectins contribute to immune evasion and cancer progression. Considering the resistance towards ICIs, current and prospective approaches for targeting glycan-lectin circuits and future prospects of these endeavors in harnessing the full potential of GNVs will also be highlighted.

Currently, immunotherapy has led to a paradigmatic shift in the treatment of many cancer types, including triple-negative breast cancer. Immunotherapy increases the efficacy of the immune system in treating cancer, with a durable effect due to immunologic memory. The PD-1 inhibitor, pembrolizumab, combined with neoadjuvant chemotherapy, improved event-free survival and is a new standard of care for patients with high-risk, early stage triple-negative breast cancer (TNBC), regardless of tumor PD-L1 expression. For metastatic TNBC, pembrolizumab combined with chemotherapy is a new standard of care for first-line therapy for PD-L1+ metastatic TNBC, and it improves overall survival. The PD-L1 inhibitor, atezolizumab, combined with nab-paclitaxel, is also approved for first-line treatment of metastatic PD-L1+ TNBC. The aim of this review is to examine the existing evidence and ongoing studies on immunotherapy in patients with early stage and metastatic triple-negative breast cancer (TNBC), including new combination strategies with several drugs, such as chemotherapy, targeted therapy, or radiation and to discuss immune checkpoint inhibitor (ICI) applications and the possibility of emerging strategies in different TNBC stages.

The tumor microenvironment (TME) and aberrant glycosylation have been suggested to play key roles in cancer. This study integrated differentially expressed genes (DEGs) and weighted gene coexpression network analysis (WGCNA) to identify tumor microenvironment-related genes and construct a TME-risk prognostic signature (TMERS) through LASSO Cox regression. After batch effect removal, 44 TME-prognosis-related genes (TMEPGs) were identified and classified into three molecular subtypes via K-means clustering. The finalized 22-gene TMERS model demonstrated robust prognostic predictive capacity in GEO datasets. The results revealed distinct immune profiles and prognostic stratifications among genetic subtypes and risk groups, confirming that the TMERS is an independent prognostic indicator for breast cancer (BRCA). Glycosyltransferase genes (GTs) have potential therapeutic relevance through immune regulation, with TMEPG member killer cell lectin like receptor B1 (KLRB1) significantly correlated with BRCA prognosis. Cellular experiments demonstrated that KLRB1 overexpression suppressed BRCA cell proliferation and migration. This work establishes a novel prognostic model for BRCA while highlighting KLRB1 as a potential biomarker, providing new insights into TME-targeted therapeutic strategies.

Recent research indicates that programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors show promise in treating triple-negative breast cancer (TNBC), but their efficacy is lower than anticipated, especially when used alone. Therefore, enhancing the anti-tumor immune response strategy for TNBC is crucial. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), involved in tumor cell regulation and a potential therapeutic target, has an undefined role in TNBC immunotherapy. In this study, we explored the inverse correlation between UCH-L1 and PD-L1 in TNBC patient tissues. Through in vitro experiments, we found that UCH-L1 negatively regulates PD-L1 by stabilizing the E3 ubiquitin ligase ariadne-1 homolog (ARIH1), which promotes PD-L1 ubiquitination and degradation. Further analysis in Balb/c mice xenograft tumors showed that UCH-L1 correlates with GZMB+/CD8+ T cell infiltration in TNBC, suggesting potential synergistic effects when combining UCH-L1 inhibitors with PD-L1 antibodies. Overall, in TNBC, UCH-L1 stabilizes ARIH1, leading to low PD-L1 expression, which may explain the limited effectiveness of immunotherapy in TNBC patients. Our mouse experiments showed improved therapeutic effects when combining UCH-L1 inhibitors with PD-L1 antibodies. These findings offer a new avenue for immunotherapy in TNBC patients.

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.

Glioblastoma (GBM) is the most malignant form of brain tumor, and GBM patients with poorer prognosis and highly immunosuppressive tumor microenvironment (TME) often exhibit PTEN deficiency in their tumor tissues. Therefore, new therapeutic strategies targeting immunosuppressive TME maybe useful in PTEN-deficient GBM.

Bioinformatics was used to assess gene expression, survival time and immunoinfiltration in PTEN-deficient GBM. CRISPR-Cas9 was used to construct gene knockout cell lines. C57BL/6 mouse orthotopic GBM models were used to conduct survival analysis and evaluate treatment effect of Ruxolitinib. Flow cytometry, immunohistochemistry, immunofluorescence and quantitative real-time PCR (qRT-PCR) to detect the polarization of macrophages. Immunoblotting, immunohistochemistry, qRT-PCR, enzyme linked immunosorbent assay, and dual-luciferase reporter assay were used to conduct mechanism research.

We identified that the elevated levels of phosphorylated STAT3 (p-STAT3) in PTEN-deficient GBM facilitate PDL1 transcription, which subsequently drives M2 polarization of macrophages. Furthermore, PTEN deficiency, along with high expression levels of STAT3 and PDL1, are associated with a shorter survival time in GBM patients. Notably, in orthotopic mouse models of GBM with PTEN deficiency, Ruxolitinib therapy reduces the levels of p-STAT3 and PDL1, inhibits the infiltration of M2 macrophages, and suppresses tumor growth.

The STAT3-PDL1 axis plays a crucial role in the M2 polarization of macrophages in PTEN-deficient GBM. The blockade of the STAT3-PDL1 axis by Ruxolitinib regulates the anti-tumor immune response and curtails tumor progression in PTEN-deficient GBM, highlighting its significant clinical implications.

Breast cancer presents a variety of subtypes due to its cellular and molecular heterogeneity. The capacity of cancer cells to proliferate, invade, and metastasize depends not only on their intrinsic characters but also on their dynamic interaction with the host tumor microenvironment (TME), which includes immune cells. Meanwhile, the infiltration of immune cells in the TME severely affects the occurrence, development, treatment, and prognosis of breast cancer. Therefore, this review aims to explore the immune invasive tumor microenvironment in different intrinsic subtypes of breast cancer. Additionally, it highlights the mechanistic influence of the infiltrating immune cells on stage-wise dynamics of breast tumorigenesis. Moreover, the present review also attempts to discern the regulatory relationship between tumor infiltrating immune cells and immune microenvironment in different molecular subtypes of breast cancer, thus, spotlighting its clinical significance.

Tumor-infiltrating lymphocyte (TIL) therapy represents a breakthrough in solid tumor treatment, addressing unmet needs for patients with limited options. While its efficacy is established in advanced melanoma, TIL therapy shows early promise in non-small cell lung cancer, breast cancer, gynecological cancers, and head and neck cancers. However, challenges such as reduced T cell infiltration, lower tumor mutational burden (TMB), immunosuppressive tumor microenvironments (TME), and toxicity associated with the TIL therapy regimen hinder its broader application in these patient groups, compared with melanoma. To address these challenges, new approaches focus on the selection of tumor-reactive TIL, optimization of TIL expansion, combination of immune checkpoint inhibitors with TIL therapy to counteract immunosuppressive microenvironments, and genetic modification of TIL to enhance persistence and functionality. Larger clinical trials are essential to validate these innovations and standardize protocols. With continued advancements, TIL therapy has the potential to redefine the treatment landscape for advanced solid cancers.

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.

Postpartum mammary gland remodeling after a pregnancy/lactation cycle is characterized by mechanisms of cell death and inflammation. Here, we show that SEMA7A promotes PD-L1 expression in immune cells of the mammary tissue during involution. These same phenotypes are mimicked in the microenvironment of SEMA7A-expressing tumors, which partially respond to αPD-1/αPD-L1 treatments in vivo. However, cells that remain after treatment are enriched for SEMA7A expression. Therefore, we tested a monoclonal antibody that directly targets SEMA7A-expressing tumors, in part, by reducing SEMA7A-mediated upregulation of PD-L1. In vivo, the SEMA7A monoclonal antibody reduces tumor growth and/or promotes complete regression of mouse mammary tumors, reduces some immunosuppressive phenotypes in the tumor microenvironment, and restores cytotoxic T cells, suggesting that SEMA7A may be a candidate for immune-based therapy for breast cancer patients.

Triple-negative breast cancer (TNBC), is a highly aggressive tumor. Formosanin C (FC) is a diosgenin with immunomodulatory and antitumor properties, the precise mechanism through which it is against TNBC remains uncertain.

Clarifying the mechanism of FC against TNBC.

The impact of FC on two TNBC cell lines for 24 h was investigated through various techniques including the CCK8 assay, flow cytometry, transwell assay, scratch tests, immunoblot assay, and immunofluorescence. To elucidate the mechanism behind the anti-TNBC effect of FC, MDA-MB-231 cells were subjected to STAT3 overexpression. Moreover, the in vivo efficacy of FC was examined using a xenograft nude mice (BALB/C). Mice were divided into the control group (equal amount of PBS), the napabucasin group (5 mg/kg) and the FC groups (1 mg/kg, 2 mg/kg). The study duration was 30 days.

FC exhibited inhibitory effects against MDA-MB-231 and Hs578T cells. FC can decrease the migratory capacity of TNBC cells by inhibiting epithelial-mesenchymal transition (EMT). Meanwhile, we demonstrated that the inhibition of phosphorylation of STAT3 (Y705) is the crucial mechanism of FC against TNBC. Moreover, FC also hindered the polarization of macrophage M2.

This study is the first to show that FC restrains the EMT of TNBC cells by obstructing the STAT3 pathway and hinders the M2 polarization of macrophages and immune evasion. Therefore, FC holds the possibility of being utilized as a therapeutic remedy for 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) continues to present a therapeutic challenge due to the fact that by definition, these cancer cells lack the expression of targetable receptors. Current treatment options include cytotoxic chemotherapy, antibody-drug conjugates (ADC), and the PD-1 checkpoint inhibitor, pembrolizumab. Due to high rates of recurrence, current guidelines for early-stage TNBC recommend either multi-agent chemotherapy or chemo-immunotherapy in all patients other than those with node-negative tumors < 0.5 cm. This approach can lead to significant long-term effects for TNBC survivors, driving a growing interest in de-escalating therapy where appropriate. Tumor infiltrating lymphocytes (TILs) represent a promising prognostic and predictive biomarker for TNBC. These diverse immune cells are present in the tumor microenvironment and within the tumor itself, and multiple retrospective studies have demonstrated that a higher number of TILs in early-stage TNBC portends a favorable prognosis. Research has also explored the potential of TIL scores to predict the response to immunotherapy. However, several barriers to the widespread use of TILs in clinical practice remain, including logistical and technical challenges with the scoring of TILs and lack of prospective trials to validate the trends seen in retrospective studies. This review will present the current understanding of the role of TILs in TNBC and discuss the future directions of TIL research.

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.

Background/Objectives: Recent clinical trials in breast cancer have demonstrated that some patients benefit from immune checkpoint blockade, though better predictive markers are needed. The accumulation of the immunomodulatory matrix proteoglycan versican (VCAN) can predict the exclusion of CD8+ tumor-infiltrating lymphocytes (TILs) in some settings and, thus, is evaluated in breast cancer here. Methods: A total of 230 breast cancers were analyzed for VCAN accumulation, VCAN proteolysis, and CD8+ TILs. CD8+ TILs were categorized based on their localization in the tumor epithelial or stromal compartments. Results: VCAN accumulation was detected in 90% of breast cancers, more commonly in ER+ tumors (93% vs. 77%; p < 0.001). MCF7 cells treated with estrogen upregulate VCAN without an enhanced expression of ADAMTS-proteases. VCAN-undetectable tumors demonstrate greater CD8+ TILs compared to VCAN-detectable tumors (p = 0.012). CD8+ T cells within TNBC tumors with high VCAN proteolysis infiltrated the epithelial compartment more often than in tumors with low VCAN proteolysis (91% vs. 42% respectively; p = 0.008). In the TCGA cohort, a strong inverse correlation between CD8A and VCAN expression was observed across subtypes. Conclusions: VCAN accumulation correlates with the exclusion of CD8+ TILs across subtypes of breast cancer, warranting further validation of VCAN accumulation and proteolysis as predictive biomarkers for breast cancer immunotherapy.

Background/Objectives: Poly (ADP-ribose) polymerase (PARP) inhibitors have shown significant efficacy in treating BRCA-mutated cancers; however, a significant proportion of patients fail to respond. Emerging evidence highlights the role of PARP in lipid metabolism, suggest-ing its modulation as a novel strategy to regulate tumor progression. Methods: In this study, lipidomics and transcriptomics analyses were conducted to elucidate the mechanisms underlying PARP inhibitor-induced ferroptosis and immune modulation in triple-negative breast cancer (TNBC). Results: We demonstrated that the PARP inhibitor Niraparib significantly reprograms lipid metabolism in TNBC cells, marked by elevated phosphatidylethanolamine (PE) and cholesterol ester (ChE) levels. This metabolic shift was mechanistically linked to upregulation of the cholesterol transporter NPC1L1 via the PARP1-RELA-NPC1L1 signaling axis, which subsequently activated the AKT pathway. Combinatorial treatment with Niraparib and either Ezetimibe (an NPC1L1 inhibitor) or AZD5363 (an AKT inhibitor) synergistically enhanced TNBC cell death by promoting ferroptosis through glutathione depletion and lipid peroxidation. Furthermore, NPC1L1 inhibition amplified PARP inhibitor-induced immune responses, increasing CD8+ T cell infiltration and cytotoxicity in tumors. Conclusions: In conclusion, our findings establish NPC1L1 as a critical mediator of PARP inhibitor efficacy and propose dual targeting of lipid metabolism, providing a new therapeutic approach for the combination treatment of TNBC.

Triple-negative breast cancer (TNBC) accounts for approximately 15% of all Breast Cancer (BC) cases with poorer prognosis and clinical outcomes compared to other BC subtypes due to greater tumor heterogeneity and few therapeutically targetable oncogenic drivers. To reveal actionable pathways for anti-cancer treatment, we use a proteomic approach to quantitatively compare the abundances of 6306 proteins across 55 formalin-fixed and paraffin-embedded (FFPE) TNBC tumors. We identified four major TNBC clusters by unsupervised clustering analysis of protein abundances. Analyses of clinicopathological characteristics revealed associations between the proteomic profiles and clinical phenotypes exhibited by each subtype. We validate the findings by inferring immune and stromal cell type composition from genome-wide DNA methylation profiles. Finally, quantitative proteomics on TNBC cell lines was conducted to identify in vitro models for each subtype. Collectively, our data provide subtype-specific insights into molecular drivers, clinicopathological phenotypes, tumor microenvironment (TME) compositions, and potential pharmacologic vulnerabilities for further investigations.

This study aimed to assess the frequency and prognostic significance of programmed cell death ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) subtypes in advanced triple-negative breast cancer (TNBC).

A database search was conducted to identify women with previously untreated locally recurrent inoperable or metastatic TNBC treated between January 2018 and December 2022. The inclusion criteria required formalin-fixed paraffin-embedded samples aged less than four years. PD-L1 expression was evaluated using the PD-L1 IHC 22C3 pharmDx assay, and the combined positive score (CPS) was calculated. TIL subtypes were assessed using immunohistochemical staining.

The study included 150 patients, with a median age of 51.5 years. The majority of patients were younger than 65 years, postmenopausal, non-white, and had metastatic TNBC. CPS≥10 was observed in 20.9% of cases, mainly in postmenopausal women. No significant differences were found in demographic characteristics and clinicopathological variables across PD-L1 subgroups. Tumors with PD-L1 CPS≥10 had higher expression of CD3+, CD4+, and CD8+ TIL subtypes. Most patients received first-line chemotherapy, with smaller proportions undergoing second, third, and fourth-line treatments. No statistically significant differences were observed in median progression-free survival (PFS) or overall survival (OS) across PD-L1 subgroups in this cohort of chemotherapy-treated patients.

This study provides insights into the expression profiles of PD-L1 and TIL subtypes in advanced TNBC. The PD-L1 CPS status did not significantly affect survival outcomes, but variations in TIL subtype composition were observed based on PD-L1 CPS status.

Programmed cell death (PCD) dynamically influences breast cancer (BC) prognosis through interactions with the tumor microenvironment (TME). We investigated 13 PCD patterns to decipher their prognostic impact and mechanistic links to TME-driven outcomes. Our study aimed to explore the complex mechanisms underlying these interactions and establish a prognostic prediction model for breast cancer.

Using TCGA and METABRIC datasets, we integrated single-sample gene set enrichment analysis (ssGSEA), weighted gene co-expression network analysis (WGCNA), and Least Absolute Shrinkage and Selection Operator (LASSO) to explore PCD-TME interactions. Multi-dimensional analyses included immune infiltration, genomic heterogeneity, and functional pathway enrichment.

Our results indicated that high apoptosis and pyroptosis activity, along with low autophagy, correlated with favorable prognosis, which was driven by enhanced anti-tumor immunity, including more M1 macrophage polarization and activated CD8+ T cells in TME. PCD-related genes could promote tumor metastasis and poor prognosis via VEGF/HIF-1/MAPK signaling and immune response, including Th1/Th2 cell differentiation, while new tumor event occurrences (metastasis/secondary cancers) were linked to specific clinical features and gene mutation spectrums, including TP53/CDH1 mutations and genomic instability. We constructed a six-gene LASSO model (BCAP31, BMF, GLUL, NFKBIA, PARP3, PROM2) to predict prognosis and identify high-risk BC patients (for five-year survival, AUC = 0.76 in TCGA; 0.74 in METABRIC). Therein, the high-risk subtype patients demonstrated a poorer prognosis, also characterized by lower microenvironment matrix and downregulated immunocyte infiltration. These six gene signatures also showed prognostic value with significant differential expression in gene and protein levels of BC samples.

Our study provided a comprehensive landscape of the cancer survival difference and related PCD-TME interaction axis and highlighted that high-apoptosis/pyroptosis states caused favorable prognosis, underlying mechanisms closely related with the TME where anti-tumor immunity would be beneficial for patient prognosis. These findings highlighted the model's potential for risk stratification in BC.

Breast cancer (BC) remains a complex and widespread problem, affecting millions of women worldwide, Among the various subtypes of BC, triple-negative breast cancer (TNBC) is particularly challenging, representing approximately 20% of all BC cases, and the survival rate of TNBC patients is generally worse than other subtypes of BC. TNBC is a heterogeneous disease characterized by lack of expression of three receptors: estrogen (ER), progesterone (PR), and human epidermal growth factor receptor 2 (HER2), resulting conventional hormonal therapies are ineffective for its management. Despite various therapeutic approaches have been explored, but no definitive solution has been found yet for TNBC. Current treatments options are chemotherapy, immunotherapy, radiotherapy and surgery, although, these therapies have some limitations, such as the development of resistance to anti-cancer drugs, and off-target toxicity, which remain primary obstacles and significant challenges for TNBC. Several findings have shown that EVs exhibit significant therapeutic promise in many diseases, and a similar important role has been observed in various types of tumor. Studies suggest that EVs may offer a potential solution for the management of TNBC. This review highlights the multifaceted roles of EVs in TNBC, emphasizing their involvement in disease progression, diagnosis and therapeutic approach, as well as their potential as biomarkers and drug delivery.

Humanized tumor mice (HTM) allow for preclinical cancer treatment studies of breast cancer (BC) under human-like conditions. This study utilized HTM for the first time to investigate potential miRNA biomarker candidates for treatment response in sera and extracellular vesicles (EVs), following X-irradiation and atezolizumab (anti-PD-L1) treatment. We identified the changes of human-specific miRNAs (miR-23b-3p and miR-155-5p) after irradiation and anti-PD-L1 treatment in HTMs with human epidermal growth factor receptor 2 positive (HER2+ BC) and triple-negative breast cancer (TNBC). The high degree of conserved, circulating free miRNA in mice and men represents a challenge of our assay; however, miRNAs with ≥2 nucleotide mismatches can be employed for human-specific analysis, and even conserved miRNAs may be utilized under clearly defined conditions of human tumor growth in HTM. A comparative analysis of extracellular vesicle miRNA cargo and free-circulating serum miRNAs revealed several exosome-specific miRNAs (miR-29b-3p, miR-34c-5p, miR-203a-3p, miR-378g, and miR-382-5p) in HTMs, which are known to play roles in BC. Our findings demonstrate that HTMs are a suitable model to identify treatment-induced changes in free-circulating and exosomal miRNAs that influence tumor progression and immunological tumor defense, both locally and at distant sites. This study presents a proof-of-principle approach to analyzing cell-free nucleotides and exosomes in a human-like, preclinical in vivo setting. Further refinements are necessary to enhance the sensitivity and the specificity of the HTM-based approach.

Metastasis-related disease is a major cause of death in canine mammary tumours (CMTs). Immunotherapy has been investigated due to the less successful outcomes of systemic therapy. This study aims to examine the expression of Programmed Cell Death Ligand-1 (PD-L1) in canine mammary tumours in dogs of Chiang Mai, Thailand, and determine the relationship between the level of mRNA expression and clinicopathologic characteristics. A total of 28 CMT samples were collected at the Small Animal Hospital, Chiang Mai University. Quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) and western blot assays were performed. The results revealed that all CMTs in this study expressed PD-L1 mRNA and PD-L1 protein. The mean relative mRNA expression showed no significant differences between groups categorized by age, tumour size, or histopathological findings. However, the mean relative mRNA expression in tumours with a TNM stage >3 was significantly lower compared to those with TNM stage ≤2. In conclusion, this study investigates the expression of PD-L1 mRNA and PD-L1 protein, particularly in malignant CMTs. The findings strongly support the potential for developing effective immunotherapy methods targeting the PD-1/PD-L1 pathway for advanced CMTs in the future. For further conclusive assessment, future studies should focus on refining immunotherapy strategies for CMT cases expressing PD-L1.

Based on the existing controversial clinical research results, this study conducted a comprehensive meta-analysis of relevant literature to clarify the benefits of immunochemotherapy (ICT)-which combines immune checkpoint inhibitors and chemotherapy (CT)-for patients with advanced triple-negative breast cancer (aTNBC).

A thorough literature search was conducted up to February 15, 2024. Subsequently, meta-analyses were performed to aggregate hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS), odds ratios (ORs) for objective response rate (ORR) and relative risks (RRs) for adverse events (AEs).

Six randomised clinical trials (RCTs) involving 3,105 patients met the inclusion criteria. In comparison with CT, ICT yielded significant enhancements in PFS (HR, 0.80; 95%CI: 0.73-0.87), OS (HR, 0.87; 95%CI: 0.80-0.96), and ORR (OR, 1.34; 95%CI: 1.15-1.55) in the intention-to-treat population. However, ICT also exhibited an increase in grade ≥3 AEs (RR, 1.11; 95%CI: 1.04-1.19) and severe AEs (RR, 1.40; 95%CI: 1.18-1.66). Subgroup analyses revealed that ICT significantly improved PFS (HR, 0.67; 95%CI: 0.58-0.77), OS (HR, 0.75; 95%CI: 0.64-0.87), and ORR (OR, 1.47; 95%CI: 1.16-1.84) within the PD-L1-positive subgroup, whereas no statistically significant differences were detected for PD-L1-negative population.

ICT demonstrates superior efficacy over conventional CT in the treatment of aTNBC, albeit accompanied by heightened toxicity. Notably, the assessment of PD-L1 status may serve as a valuable biomarker in discerning aTNBC patients who are particularly predisposed to derive benefit from ICT.

CRD42024513270.

Triple-negative breast cancer (TNBC), characterized by high heterogeneity and invasiveness. Currently, inducing immunogenic cell death (ICD) of tumor cells through approaches such as radiotherapy and chemotherapy is an effective strategy to enhance the response to anti-programmed death-ligand 1 antibody (aPD-L1) therapy in TNBC. However, radiotherapy and chemotherapy treatments often upregulate PD-L1 expression in tumor cells, thereby weakening the tumor cells' response to aPD-L1. Celastrol exhibits broad-spectrum and potent anti-tumor activity, efficiently inducing ICD without increasing PD-L1 levels in tumor cells.

This study aims to elucidate the tumor-targeting effects of celastrol-loaded liposomes and its synergistic efficacy and mechanism of action in combination with aPD-L1 against TNBC.

The Rg3 liposomes loaded with celastrol (Cel-Rg3-Lp) were prepared using the thin-film hydration method. BALB/c mice were utilized to establish an in situ breast cancer model. Mice were intravenously injected with Cel-Rg3-Lp at a dosage of celastrol 1 mg/kg once every two days for a total of 7 injections. Flow cytometry, western blot, and immunofluorescence techniques were employed to investigate the synergistic effects and mechanisms of Cel-Rg3-Lp combined with aPD-L1 in the treatment of TNBC.

The findings of this study demonstrate that after 7 administrations of Cel-Rg3-Lp (1 mg/kg celastrol, intravenously), significant anti-tumor effects are observed, including the recruitment of CD8+T cells and dendritic cells (DCs), while reducing the infiltration of immunosuppressive cells. The therapeutic efficacy was further enhanced when combined with aPD-L1. Additionally, Cel-Rg3-Lp markedly downregulated glucose-regulated protein 78 (GRP78) expression, thereby inducing ICD in tumor cells.

This study successfully constructed a multifunctional liposome and proposed a mechanism for inducing ICD through the GRP78-endoplasmic reticulum stress pathway. The liposome downregulates GRP78, triggering endoplasmic reticulum stress in tumor cells, inducing ICD, activating DCs, and enhancing antigen presentation to T cells. This improves the tumor immune microenvironment and provides a theoretical foundation for combining Cel-Rg3-Lp with aPD-L1 in the treatment of TNBC. This mechanism opens unique prospects for using celastrol in TNBC therapy and enhancing the effectiveness of immunotherapy.

Breast cancer (BC) remains a significant global health challenge due to its complex biology, which complicates both diagnosis and treatment. Immunotherapy and cancer vaccines have emerged as promising alternatives, harnessing the body's immune system to precisely target and eliminate cancer cells. However, several key factors influence the selection and effectiveness of these therapies, including BC subtype, tumor mutational burden (TMB), tumor-infiltrating lymphocytes (TILs), PD-L1 expression, HER2 resistance, and the tumor microenvironment (TME). BC subtypes play a critical role in shaping treatment responses. Triple-negative breast cancer (TNBC) exhibits the highest sensitivity to immunotherapy, while HER2-positive and hormone receptor-positive (HR+) subtypes often require combination strategies for optimal outcomes. High TMB enhances immune responses by generating neoantigens, making tumors more susceptible to immune checkpoint inhibitors (ICIs); whereas, low TMB may indicate resistance. Similarly, elevated TIL levels are associated with better immunotherapy efficacy, while PD-L1 expression serves as a key predictor of checkpoint inhibitor success. Meanwhile, HER2 resistance and an immunosuppressive TME contribute to immune evasion, highlighting the need for multi-faceted treatment approaches. Current breast cancer immunotherapies encompass a range of targeted treatments. HER2-directed therapies, such as trastuzumab and pertuzumab, block HER2 dimerization and enhance antibody-dependent cellular cytotoxicity (ADCC), while small-molecule inhibitors, like lapatinib and tucatinib, suppress HER2 signaling to curb tumor growth. Antibody-drug conjugates (ADCs) improve tumor targeting by coupling monoclonal antibodies with cytotoxic agents, minimizing off-target effects. Meanwhile, ICIs, including pembrolizumab, restore T-cell function, and CAR-macrophage (CAR-M) therapy leverages macrophages to reshape the TME and overcome immunotherapy resistance. While immunotherapy, particularly in TNBC, has demonstrated promise by eliciting durable immune responses, its efficacy varies across subtypes. Challenges such as immune-related adverse events, resistance mechanisms, high costs, and delayed responses remain barriers to widespread success. Breast cancer vaccines-including protein-based, whole-cell, mRNA, dendritic cell, and epitope-based vaccines-aim to stimulate tumor-specific immunity. Though clinical success has been limited, ongoing research is refining vaccine formulations, integrating combination therapies, and identifying biomarkers for improved patient stratification. Future advancements in BC treatment will depend on optimizing immunotherapy through biomarker-driven approaches, addressing tumor heterogeneity, and developing innovative combination therapies to overcome resistance. By leveraging these strategies, researchers aim to enhance treatment efficacy and ultimately improve patient outcomes.

Triple-negative breast cancer (TNBC) is a highly heterogeneous and aggressive subtype of breast cancer that faces therapeutic challenges due to a shortage of effective targeted therapies. The complex biology of TNBC renders its clinical management fraught with difficulties, especially regarding the immune microenvironment of the tumor. In recent years, long non-coding RNAs (lncRNAs) have been recognized as important gene regulators with key roles in tumor development and microenvironmental regulation. Previous studies have shown that lncRNAs play important roles in the immune microenvironment of TNBC, including the regulation of tumor immune escape and the function of tumor-infiltrating immune cells. However, despite the increasing research on lncRNAs, there are still many unanswered questions, such as their specific mechanism of action and how to effectively utilize them as therapeutic targets. Therefore, the aim of this study was to review the mechanisms of lncRNAs in the TNBC immune microenvironment, explore their regulatory roles in tumor immune escape and immune cell infiltration, and explore their prospects as potential therapeutic targets. By integrating the latest research results, this study aims to provide new ideas and directions for future TNBC treatment.

Recent breakthroughs in tumor immunotherapy have confirmed the capacity of the immune system to fight several cancers. The effective means of treating cancer involves accelerating the death of tumor cells and improving patient immunity. Dynamic changes in the tumor immune microenvironment alter the actual effects of anti-tumor drug production and may trigger favorable or unfavorable immune responses by modulating tumor-infiltrating lymphocytes. Notably, CD8+ T cells are one of the primary tumor-infiltrating immune cells that provide anti-tumor response. Tumor cells and tumor stem cells will resist or evade destruction through various mechanisms as CD8+ T cells exert their anti-tumor function. This paper reviews the research on the regulation of tumor development and prognosis by cancer stem cells that directly or indirectly alter the role of tumor-infiltrating CD8+ T cells. We also discuss related immunotherapy strategies.

Major advances have been achieved in the characterization of primary breast cancer genomic profiles. Limited information is available on the genomic profile of tumors originating from different metastatic locations in recurrent/metastatic (R/M) breast cancer, especially in Asian patients. This study aims to decipher the mutational profiles of primary and R/M breast cancer in Chinese patients using next-generation sequencing.

A total of 563 breast cancer patients were enrolled, and 590 tumor tissues and matched peripheral blood samples were collected and subjected to targeted sequencing with a panel of 1,021 cancer-related genes. The mutation spectrum, DNA damage response (DDR) genes, commonly altered signal pathways, and immunotherapy-related markers were compared between primary and R/M breast cancer. The molecular differences between our cohort and the Memorial Sloan Kettering Cancer Center (MSKCC) dataset were also explored.

A total of 361 samples from primary and 229 samples from R/M breast cancer were analyzed. BRCA2, ATRX, and ATM were more frequently observed in R/M lesions among the 36 DDR genes. An ESR1 mutation and PD-L1 and PD-L2 amplification were enriched in R/M breast cancer (all p<0.05). Compared with the MSKCC dataset, we recruited more patients diagnosed at age 50 or younger and more patients with triple-negative breast cancer (TNBC) subtypes. The TNBC patients in our dataset had a higher percentage of PD-L1 amplification in metastasis tumors (p<0.05).

This study revealed the distinctive mutational features of primary and R/M tumors in Chinese breast cancer patients, which are different from those from Western countries. The enrichment of PD-L1 amplification in metastatic TNBC indicates the necessity to re-biopsy metastatic tumors for immunotherapy.

Triple-negative breast cancer (TNBC) is an aggressive metastatic subtype of BC that frequently develops chemoresistance. Immune checkpoint blockers (ICB) have led to breakthroughs in TNBC treatment. This study aimed to explore research trends and public interest in ICB interventions for TNBC.

We searched the Web of Science Core Collection (WoSCC) database for publications related to ICB for TNBC from 2003 to 2024. VOSviewer, CiteSpace, and R package "bibliometrix" were used to analyze the characteristics of ICB publications in TNBC from a quantitative and qualitative perspective and to visualize the results to comprehensively present the research trends in this field.

After removing duplicates, 2698 publications were included. The New England Journal of Medicine may be the leading and influential in the field of ICB in TNBC according to data on the total number of publications, number of citations, and impact factors. Its article entitled "Atezolizumab and Nab-Paclitaxel in Advanced TNBC" is 1 of the most cited articles. Keyword analysis showed that current research hotspots in this field are tumor microenvironment, complete pathological response, neoadjuvant chemotherapy, and PARP inhibitors. Future research hotspots may include the PD-L1 inhibitor durvalumab and antibody-drug conjugates (ADC).

This study revealed that ICB therapy for TNBC is a rapidly evolving and high-profile topic. Future research should focus on the optimal selection of different targets for ICB in combination with neoadjuvant chemotherapy, ADC, and poly ADP-ribose polymerase inhibitors to treat TNBC.

Mutations in the tumor suppressor genes BRCA1 and BRCA2 are associated with the triple-negative breast cancer phenotype, particularly aggressive and hard-to-treat tumors lacking estrogen, progesterone, and human epidermal growth factor receptor 2. This research aimed to understand the metabolic and genetic links behind BRCA1 and BRCA2 mutations and investigate their relationship with effective therapies. Using the Cytoscape software, two networks were generated through a bibliographic analysis of articles retrieved from the PubMed-NCBI database. We identified 98 genes deregulated by BRCA mutations, and 24 were modulated by therapies. In particular, BIRC5, SIRT1, MYC, EZH2, and CSN2 are influenced by BRCA1, while BCL2, BAX, and BRIP1 are influenced by BRCA2 mutation. Moreover, the study evaluated the efficacy of several promising therapies, targeting only BRCA1/BRCA2-mutated cells. In this context, CDDO-Imidazolide was shown to increase ROS levels and induce DNA damage. Similarly, resveratrol decreased the expression of the anti-apoptotic gene BIRC5 while it increased SIRT1 both in vitro and in vivo. Other specific drugs were found to induce apoptosis selectively in BRCA-mutated cells or block cell growth when the mutation occurs, i.e., 3-deazaneplanocin A, genistein or daidzein, and PARP inhibitors. Finally, over-representation analysis on the genes highlights ferroptosis and proteoglycan pathways as potential drug targets for more effective treatments.

Previous literature extensively explored biomarkers to personalize treatment for breast cancer patients. The clinical need is especially high in patients with triple-negative breast cancer (TNBC) due to its aggressive nature and limited treatment modalities. This review aims to evaluate the value of tumor-infiltrating lymphocytes (TILs) and tumor-stroma ratio (TSR) as prognostic biomarkers in TNBC patients and assess their clinical potential. A literature search was conducted in PubMed, Embase, Emcare, Web of Science, and Cochrane Library. Papers comparing survival outcomes of TNBC patients with low/high or negative/positive TSR and immune cells were included. The most frequently mentioned subgroups of TILs were selected and reported in this review. Data from 43 articles on TILs and eight articles on TSR were included. Among TNBC patients, high CD8 expression was generally associated with better survival. Notable, the poor survival outcomes were related to high intra-tumoral PD-L1 expression, whereas high stromal PD-L1 expression more often was correlated with favorable outcomes. For the TSR, a high amount of stroma in the primary tumor of TNBC patients was consistently associated with worse survival. This review highlights that a high number of CD8-positive T-cells is a promising prognostic factor for TNBC patients. PD-L1 expression analyzed for intra-tumoral and stromal expression separately reports strong but contrasting information. Finally, the TSR shows potential to be an important prognostic marker, especially for TNBC patients. Utilizing both biomarkers, either on itself or combined, could enhance clinical decision-making and personalization of treatment.

Gamabufotalin (CS-6), a main active compound derived from Chinese medicine Chansu, exhibits a robust inhibitory effect on programmed death-ligand 1 (PD-L1) in triple-negative breast cancer (TNBC) cells. Despite its potential for tumor therapy, the medical application of CS-6 is constrained by its hydrophobic nature, lack of targeting capability, and weak immunogenic cell death (ICD) effect. To address these limitations and improve the therapeutic efficiency of this drug against metastatic TNBC, we designed a new kind of CS-6@CPB-S.lux that integrates carboxy-Prussian blue nanoparticles (CPB NPs), CS-6, and attenuated Salmonella typhimurium (S.lux) for TNBC therapy. In vitro and in vivo results have confirmed that CS-6@CPB NPs were efficiently delivered to neoplastic tissue by the tumor hypoxic chemotaxis property of S.lux, wherein the nanomedicine induced significant tumor cell necroptosis and apoptosis via photothermal therapy (PTT) of CPB NPs and chemotherapy of CS-6, which elicited ICD and inhibited PD-L1 expression, resulting in dendritic cells (DCs) maturation and effector T cells activation to comprehensively eliminate tumors. Additionally, the CS-6@CPB-S.lux + Laser treatment significantly transformed the immunosuppressive tumor microenvironment (TME), enhancing antitumor immunity through promoting the polarization of tumor-associated macrophages into antitumorigenic M1 and reducing Tregs recruitment. Consequently, this comprehensive therapy not only inhibited primary and abscopal tumor progression but also prevented TNBC metastasis, which significantly prolonged survival time in animal models. In summary, these findings indicated an alternative approach for metastatic TNBC therapy.