SNX16 is required for hepatocellular carcinoma survival via modulating the EGFR-AKT signaling pathway.

Sorting nexin 16 (SNX16), a pivotal sorting nexin, emerges in tumor progression complexity, fueling research interest. However, SNX16's biological impact and molecular underpinnings in hepatocellular carcinoma (HCC) remain elusive. This study probes SNX16's function, clinical relevance via mRNA, and protein expression in HCC. Overexpression/knockdown assays of SNX16 were employed to elucidate impacts on HCC cell invasion, proliferation, and EMT. Additionally, the study delved into SNX16's regulation of the EGFR-AKT signaling cascade mechanism. SNX16 overexpression in HCC correlates with poor patient survival; enhancing proliferation, migration, invasion, and tumorigenicity, while SNX16 knockdown suppresses these processes. SNX16 downregulation curbs phospho-EGFR, dampening AKT signaling. EGFR suppression counters SNX16-overexpression-induced HCC proliferation, motility, and invasiveness. Our findings delineate SNX16's regulatory role in HCC, implicating it as a prospective therapeutic target.

KLF4 Induces Colorectal Cancer by Promoting EMT via STAT3 Activation.

OBJECTIVE: Krüppel-like factor 4 (KLF4) has been demonstrated to exert a pro-carcinogenic effect in solid tissues. However, the precise biological function and underlying mechanisms in colorectal cancer (CRC) remains elucidated. AIMS: To investigate whether KLF4 participates in the proliferation and invasion of CRC. METHODS: The expression of KLF4 was investigated using immunohistochemistry and immunoblotting. The clinical significance of KLF4 was evaluated. Furthermore, the effect of inhibiting or overexpressing KLF4 on tumor was examined. Immunoblotting and qPCR were used to detect Epithelial-mesenchymal transition-related proteins levels. Additionally, the molecular function of KLF4 is related to the STAT3 signaling pathway and was determined through JASPAR, GSEA analysis, and in vitro experiments. RESULTS: KLF4 exhibits down-regulated expression in CRC and is part of the vessel invasion, TNM stage, and worse prognosis. In vitro studies have shown that KLF4 promotes cellular proliferation and invasion, as well as EMT processes. Xenograft tumor models confirmed the oncogenic role of KLF4 in nude mice. Furthermore, GSEA and JASPAR databases analysis reveal that the binding of KLF4 to the signal transducer and activator of transcription 3 (STAT3) promoter site induces activation of p-STAT3 signaling. Subsequent targeting of STAT3 confirmed its pivotal role in mediating the oncogenic effects exerted by KLF4. CONCLUSION: The study suggests that KLF4 activates STAT3 signaling, inducing epithelial-mesenchymal transition, thereby promoting CRC progression.

Modulating Intracellular Dynamics for Optimized Intracellular Release and Transcytosis Equilibrium.

Active transcytosis-mediated nanomedicine transport presents considerable potential in overcoming diverse delivery barriers, thereby facilitating tumor accumulation and penetration. Nevertheless, the persistent challenge lies in achieving a nuanced equilibrium between intracellular interception for drug release and transcytosis for tumor penetration. In this study, a comprehensive exploration is conducted involving a series of polyglutamine-paclitaxel conjugates featuring distinct hydrophilic/hydrophobic ratios (HHR) and tertiary amine-oxide proportions (TP) (OPGA-PTX). The screening process, meticulously focused on delineating their subcellular distribution, transcytosis capability, and tumor penetration, unveils a particularly promising candidate denoted as OPPX, characterized by an HHR of 10:1 and a TP of 100%. OPPX, distinguished by its rapid cellular internalization through multiple endocytic pathways, selectively engages in trafficking to the Golgi apparatus for transcytosis to facilitate accumulation within and penetration throughout tumor tissues and simultaneously sorted to lysosomes for cathepsin B-activated drug release. This study not only identifies OPPX as an exemplary nanomedicine but also underscores the feasibility of modulating subcellular distribution to optimize the active transport capabilities and intracellular release mechanisms of nanomedicines, providing an alternative approach to designing efficient anticancer nanomedicines.

Targeting initial tumour-osteoclast spatiotemporal interaction to prevent bone metastasis.

Bone is the most common site of metastasis, and although low proliferation and immunoediting at the early stage make existing treatment modalities less effective, the microenvironment-inducing behaviour could be a target for early intervention. Here we report on a spatiotemporal coupling interaction between tumour cells and osteoclasts, and named the tumour-associated osteoclast 'tumasteoclast'-a subtype of osteoclasts in bone metastases induced by tumour-migrasome-mediated cytoplasmic transfer. We subsequently propose an in situ decoupling-killing strategy in which tetracycline-modified nanoliposomes encapsulating sodium bicarbonate and sodium hydrogen phosphate are designed to specifically release high concentrations of hydrogen phosphate ions triggered by tumasteoclasts, which depletes calcium ions and forms calcium-phosphorus crystals. This can inhibit the formation of migrasomes for decoupling and disrupt cell membrane for killing, thereby achieving early prevention of bone metastasis. This study provides a research model for exploring tumour cell behaviour in detail and a proof-of-concept for behaviour-targeting strategy.

Efficacy of Transcutaneous Electrical Acupoint Stimulation on Chronic Postsurgical Pain After Video-Assisted Thoracoscopic Lobectomy: Study Protocol for a Prospective Randomized Controlled Trial.

INTRODUCTION: Patients undergoing video-assisted thoracoscopic lobectomy (VATL) often experience chronic postsurgical pain (CPSP). Postoperative pain can affect the recovery of postoperative lung function, prolong postoperative recovery time, and increase patient hospitalization expenses. Transcutaneous electrical acupoint stimulation (TEAS) is an alternative therapy based on acupuncture that has shown promise in postoperative recovery and pain management across various medical fields. However, research specifically focused on the improvement of CPSP after VATL is currently lacking. The purpose of this study is to evaluate whether TEAS can effectively reduce the severity and occurrence of chronic postsurgical pain in patients undergoing VATL. By investigating the potential benefits of TEAS in mitigating CPSP after VATL, this study aims to provide valuable clinical evidence to support the integration of TEAS into postoperative care protocols for patients undergoing VATL. METHODS: This study is a prospective, single-center, double-blinded, randomized controlled trial to be conducted at the 920th Hospital of Joint Logistics Support Force. Eighty patients undergoing VATL will be randomly divided into an experimental group (TEAS group) and a control group (sham group). The experimental group will receive TEAS at bilateral PC6, LI4, LR3, LU5, TE5, and LI11. The control group will not receive TEAS at the same acupoints. Both groups will receive TEAS or no TEAS before anesthesia induction and 1-7 days after surgery, with each session lasting 30 min. PLANNED OUTCOMES: The primary outcome will be the incidence of CPSP at 3 months after surgery. Secondary outcomes will include the incidence of CPSP at 6 months after surgery, the numerical rating scale (NRS) scores at 3 and 6 months after surgery, as well as the NRS scores at 24, 48, and 72 h after surgery, remifentanil consumption during general anesthesia, demand for rescue analgesics, number and duration of indwelling chest tubes, incidence of postoperative nausea and vomiting, and changes of norepinephrine (NE), cortisol (Cor), tumor necrosis factor (TNF- α), and interleukin 6 (IL-6) in serum. TRIAL REGISTRATION: ChiCTR2300069458. Registered on March 16, 2023.

Efficacy and safety of ketamine as an adjuvant to regional anesthesia: A systematic review and meta-analysis of randomized controlled trials.

STUDY OBJECTIVE: To identify whether adding ketamine to the local anesthetics (LA) in the regional anesthesia could prolong the duration of analgesia. DESIGN: A Systematic review and meta-analysis of randomized controlled trials. SETTING: The major dates were obtained in the operating room and the postoperative recovery ward. PATIENTS: A total of 1011 patients at ASA physical status I and II were included in the analysis. Procedure performed including cesarean section, orthopedic, radical mastectomy, urological or lower abdominal surgery and intracavitary brachytherapy implants insertion. INTERVENTIONS: After an extensive search of the electronic database, patients received regional anesthesia combined or not combined general anesthesia and with or without adding ketamine to LA were included in the analysis. The regional anesthesia includes spinal anesthesia, brachial plexus block, pectoral nerve block, transversus abdominis plane block and femoral and sciatic nerve block. MEASUREMENT: The primary outcome was the duration of analgesia. Secondary outcomes were the duration and onset time of motor and sensory block as well as the ketamine-related adverse effect. Data are expressed in mean differences in continuous data and odds ratios (OR) for dichotomous data with 95% confidence intervals. The risk of bias of the included studies was evaluated using the revised Cochrane risk of bias tool for randomized trials. The quality of evidence for each outcome was rated according to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) Working Group system. MAIN RESULT: Twenty randomized controlled trials were included in the analysis. When ketamine was used as an adjuvant to LA, the duration of analgesia could be prolonged(172.21 min, 95% CI, 118.20 to 226.22; P<0.00001, I2 = 98%), especially in the peripheral nerve block(366.96 min, 95% CI, 154.19 to 579.74; P = 0.0007, I2 = 98%). Secondary outcomes showed ketamine could prolong the duration of sensory block(29.12 min, 95% CI, 10.22 to 48.01; P = 0.003, I2 = 96%) but no effect on the motor block(6.94 min, 95% CI,-2.65 to 16.53;P = 0.16, I2 = 84%), the onset time of motor and sensory block (motor onset time, -1.17 min, 95% CI, -2.67 to 0.34; P = 0.13, I2 = 100%; sensory onset time, -0.33 min, 95% CI,-0.87 to 0.20; P = 0.23, I2 = 96%) as well as the ketamine-related adverse effect(OR, 1.97, 95% CI,0.93 to 4.17;P = 0.08, I2 = 57%). CONCLUSION: This study indicates that ketamine could be an ideal adjuvant to local anesthetics regardless of the types of anesthesia. Overall, the quality of the evidence is low.

KLF3 promotes colorectal cancer growth by activating WNT1.

OBJECTIVE: The function of Kruppel-like factor 3 (KLF3) remains largely unexplored in colorectal cancer (CRC). METHODS: KLF3 expression in CRC was assessed through qPCR, western blotting, immunohistochemical assays, and The Cancer Genome Atlas (TCGA) database. The tumor-promoting capacity of KLF3 was explored by performing in vitro functional experiments using CRC cells. A subcutaneous nude mouse tumor assay was employed to evaluate tumor growth. To further elucidate the interaction between KLF3 and other factors, luciferase reporter assay, agarose gel electrophoresis, and ChIP analysis were performed. RESULTS: KLF3 was downregulated in CRC tissue and cells. Silencing of KLF3 increased the potential of CRC cells for proliferation, migration, and invasion, while its activation decreased these processes. Downregulated KLF3 was associated with accelerated tumor growth in vivo. Mechanistically, KLF3 was discovered to target the promoter sequence of WNT1. Consequently, the diminished expression of KLF3 led to the buildup of WNT1 and the WNT/ß-catenin pathway activation, consequently stimulating the progression of CRC. CONCLUSIONS: This investigation suggests that the involvement of KLF3/WNT1 regulatory pathway contributes to the progression of CRC, thereby emphasizing its promise as an important focus for future therapies aimed at treating CRC.

Artificially reprogrammed stem cells deliver transcytosable nanocomplexes for improved spinal cord repair.

Stem cell transplantation holds great promise for restoring function after spinal cord injury (SCI), but its therapeutic efficacy heavily depends on the innate capabilities of the cells and the microenvironment at the lesion site. Herein, a potent cell therapeutic (NCs@SCs) is engineered by artificially reprogramming bone marrow mesenchymal stem cells (BMSCs) with oxidation-responsive transcytosable gene-delivery nanocomplexes (NCs), which endows cells with robust oxidative stress resistance and improved cytokine secretion. NCs@SCs can accumulate in the injured spinal cord after intravenous administration via chemotaxis and boost successive transcytosis to deliver NCs to neurons, augmenting ciliary neurotrophic factor (CNTF) production in both BMSCs and neurons in response to elevated ROS levels. Furthermore, NCs@SCs can actively sense and eliminate ROS and re-educate recruited M1-like macrophages into the anti-inflammatory M2 phenotype via a paracrine pathway, ultimately reshaping the inflammatory microenvironment. Synergistically, NCs@SCs exhibit durable survival and provide neuroprotection against secondary damage, enabling significant locomotor function recovery in SCI rats. Transcriptome analysis reveals that regulation of the ROS/MAPK signaling pathway is involved in SCI therapy by NCs@SCs. This study presents a nanomaterial-mediated cell-reprogramming approach for developing live cell therapeutics, showing significant potential in the treatment of SCI and other neuro-injury disorders.

Electrical stimulation induces anti-tumor immunomodulation via a flexible microneedle-array-integrated interdigital electrode.

Immunotherapy has revolutionized cancer therapy, using chemical or biological agents to reinvigorate the immune system. However, most of these agents have poor tumor penetration and inevitable side effects that complicate therapeutic outcomes. Electrical stimulation (ES) is a promising alternative therapy against cancers that does not involve chemical or biological agents but is limited in the fabrication and operation of complex micrometer-scale ES devices. Here, we present an optically microprinted flexible interdigital electrode with a gold-plated polymer microneedle array to generate alternating electric fields for cancer treatment. A flexible microneedle-array-integrated interdigital electrode (FMIE) was fabricated by combining optical 3D microprinting and electroless plating processes. FMIE-mediated ES of cancer cells induced necrotic cell death through mitochondrial Ca2+ overload and increased intracellular reactive oxygen species (ROS) production. This led to the release of damage-associated molecular patterns that activated the immune response and potentiated immunogenic cell death (ICD). FMIE-based ES has an excellent safety profile and systemic anti-tumor effects, inhibiting the growth of primary and distant tumors as well as melanoma lung metastasis. FMIE-based ES-driven cancer immunomodulation provides a new pathway for drug-free cancer therapy.

Tumor Abnormality-Oriented Nanomedicine Design.

Anticancer nanomedicines have been proven effective in mitigating the side effects of chemotherapeutic drugs. However, challenges remain in augmenting their therapeutic efficacy. Nanomedicines responsive to the pathological abnormalities in the tumor microenvironment (TME) are expected to overcome the biological limitations of conventional nanomedicines, enhance the therapeutic efficacies, and further reduce the side effects. This Review aims to quantitate the various pathological abnormalities in the TME, which may serve as unique endogenous stimuli for the design of stimuli-responsive nanomedicines, and to provide a broad and objective perspective on the current understanding of stimuli-responsive nanomedicines for cancer treatment. We dissect the typical transport process and barriers of cancer drug delivery, highlight the key design principles of stimuli-responsive nanomedicines designed to tackle the series of barriers in the typical drug delivery process, and discuss the "all-into-one" and "one-for-all" strategies for integrating the needed properties for nanomedicines. Ultimately, we provide insight into the challenges and future perspectives toward the clinical translation of stimuli-responsive nanomedicines.

"One-for-All" approach: a black technology for nanomedicine development?

Cancer nanomedicines require different, even opposite, properties to voyage the cascade drug delivery process involving a series of biological barriers. Currently-approved nanomedicines can only alleviate adverse effects but cannot improve patient survival because they fail to meet all the requirements. Therefore, nanocarriers with synchronized functions are highly requisite to capacitate efficient drug delivery and enhanced therapeutic efficacies. This perspective article summarizes recent advances in the two main strategies for nanomedicine design, the All-in-One approach (integration of all the functions in one system) and the One-for-All approach (one functional group with proper affinity enables all the functions), and presents our views on future nanomedicine development.

Tumor permeable self-delivery nanodrug targeting mitochondria for enhanced chemotherapy.

Drug self-delivery systems (DSDSs) have been extensively exploited to enhance drug loading capacity and avoid excipient-related toxicity issues. However, deficient tumor targeting, inferior tumor permeability, prominent burst release, and nonspecific subcellular distribution remain major obstacles. Herein, we reported a ROS-responsive amphiphilic prodrug (CPT-S-NO) synthesized by the conjugation of zwitterionic tertiary amine-oxide (TAO) moiety and hydrophobic camptothecin (CPT) through a thioether linkage, which formed a nanoparticulate DSDS in an aqueous solution. CPT-S-NO, compared with CPT-11 and the water-soluble TAO-modified CPT prodrug (CPT-NO), exhibited prolonged blood circulation, enhanced tumor accumulation, deep tumor penetration, efficient mitochondrial targeting, and ROS-activated drug release to induce mitochondrial dysfunction, corporately conducing to the superior antitumor efficacy in vivo. This TAO decoration strategy promises potential applications in designing multipotent DSDSs for various drugs.

Dual Synergistic Tumor-Specific Polymeric Nanoparticles for Efficient Chemo-Immunotherapy.

Chemo-immunotherapy has made significant progress in cancer treatment. However, the cancer cell self-defense mechanisms, including cell cycle checkpoint and programmed cell death-ligand 1 (PD-L1) upregulation, have greatly hindered the therapeutic efficacy. Herein, norcantharidin (NCTD)-platinum (Pt) codelivery nanoparticles (NC-NP) with tumor-sensitive release profiles are designed to overcome the self-defense mechanisms via synergistic chemo-immunotherapy. NC-NP remains stable under normal physiological conditions but quickly releases 1,2-diaminocyclohexane-platinum(II) (DACHPt, a parent drug of oxaliplatin) and NCTD in response to the tumor acidity. NCTD inhibits protein phosphatase 2A (PP2A) activity to relieve cell cycle arrest and downregulates the tumor PD-L1 expression to disrupt the programmed cell death-1 (PD-1)/PD-L1 interaction, synergistically enhancing Pt-based chemotherapy and immunogenic cell death-induced immunotherapy. As a result, NC-NP exhibits potent synergistic cytotoxicity and promotes T cell recruitment to generate robust antitumor immune responses. The dual synergism exhibits potent antitumor activity against orthotopic 4T1 tumors, providing a promising chemo-immunotherapy paradigm for cancer treatment.

Esterase-Labile Quaternium Lipidoid Enabling Improved mRNA-LNP Stability and Spleen-Selective mRNA Transfection.

Ionizable cationic lipids are recognized as an essential component of lipid nanoparticles (LNPs) for messenger RNA (mRNA) delivery but can be confounded by low lipoplex stability with mRNA during storage and in vivo delivery. Herein, the rational design and combinatorial synthesis of esterase-triggered decationizable quaternium lipid-like molecules (lipidoids) are reported to develop new LNPs with high delivery efficiency and improved storage stability. This top lipidoid carries positive charges at the physiological condition but promptly acquires negative charges in the presence of esterase, thus permitting stable mRNA encapsulation during storage and in vivo delivery while balancing efficient mRNA release in the cytosol. An optimal LNP formulation is then identified through orthogonal optimization, which enables efficacious mRNA transfection selectively in the spleen following intravenous administration. LNP-mediated delivery of ovalbumin (OVA)-encoding mRNA induces efficient antigen expression in antigen-presenting cells and elicits robust antigen-specific immune responses against OVA-transduced tumors. The work demonstrates the potential of decationizable quaternium lipidoids for spleen-selective RNA transfection and cancer immunotherapy.

Role of Micelle Size in Cell Transcytosis-Based Tumor Extravasation, Infiltration, and Treatment Efficacy.

Transcytosis-based active transport of cancer nanomedicine has shown great promise for enhancing its tumor extravasation and infiltration and antitumor activity, but how the key nanoproperties of nanomedicine, particularly particle size, influence the transcytosis remains unknown. Herein, we used a transcytosis-inducing polymer, poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA), and fabricated stable OPDEA-based micelles with different sizes (30, 70, and 140 nm in diameter) from its amphiphilic block copolymer, OPDEA-block-polystyrene (OPDEA-PS). The study of the micelle size effects on cell transcytosis, tumor extravasation, and infiltration showed that the smallest micelles (30 nm) had the fastest transcytosis and, thus, the most efficient tumor extravasation and infiltration. So, the 7-ethyl-10-hydroxyl camptothecin (SN38)-conjugated OPDEA micelles of 30 nm had much enhanced antitumor activity compared with the 140 nm micelles. These results are instructive for the design of active cancer nanomedicine.

Guanidine-modified nanoparticles as robust BTZ delivery carriers and activators of immune responses.

Dendritic cells (DCs), the primary antigen-presenting cells in the immune system, play a critical role in regulating tumor immune responses. However, the tumor immunosuppressive microenvironment severely impedes the process of antigen-presenting and DC maturation, thereby limiting the efficacy of cancer immunotherapy. In this work, a pH-responsive polymer nanocarrier (PAG) modified with aminoguanidine (AG) was constructed for the efficient delivery of bortezomib (BTZ) through bidentate hydrogen bonds and electrostatic adsorption formed between guanidine groups of PAG and boronic acid groups of BTZ. The obtained PAG/BTZ nanoparticles exhibited pH-responsive release of BTZ and AG in the acidic tumor microenvironment. On the one hand, BTZ induced potent immune activation by eliciting immunogenic cell death (ICD) and releasing damage-associated molecular patterns. On the other hand, the cationic AG significantly promoted antigen uptake by DCs and activated DC maturation. As a result, PAG/BTZ significantly stimulated tumoral infiltration of cytotoxic T lymphocytes (CTLs) and triggered robust antitumor immune responses. Thus, it showed potent antitumor efficacy when synergizing with an immune checkpoint-blocking antibody.

Aminopeptidase N-Responsive Conjugates with Tunable Charge-Reversal Properties for Highly Efficient Tumor Accumulation and Penetration.

Tumor enzyme-responsive charge-reversal carriers can induce efficient transcytosis and lead to efficient tumor infiltration and potent anticancer efficacy. However, the correlations of molecular structure with charge-reversal property, tumor penetration, and drug delivery efficiency are unknown. Herein, aminopeptidase N (APN)-responsive conjugates were synthesized to investigate these correlations. We found that the monomeric unit structure and the polymer chain structure determined the enzymatic hydrolysis and charge-reversal rates, and accordingly, the transcytosis and tumor accumulation and penetration of the APN-responsive conjugates. The conjugate with moderate APN responsiveness balanced the in vitro transcytosis and in vivo overall drug delivery process and achieved the best tumor delivery efficiency, giving potent antitumor efficacy. This work provides new insight into the design of tumor enzyme-responsive charge-reversal nanomedicines for efficient cancer drug delivery.

The tumor EPR effect for cancer drug delivery: Current status, limitations, and alternatives.

Over the past three decades, the enhanced permeability and retention (EPR) effect has been considered the basis of tumor-targeted drug delivery. Various cancer nanomedicines, including macromolecular drugs, have been designed to utilize this mechanism for preferential extravasation and accumulation in solid tumors. However, such nanomedicines have not yet achieved convincing therapeutic benefits in clinics. Increasing evidence suggests that the EPR effect is over-represented in human tumors, especially in metastatic tumors. This review covers the evolution of the concept, the heterogeneity and limitation of the EPR effect in clinical realities, and prospects for alternative strategies independent of the EPR effect.

Transcytosis-enabled active extravasation of tumor nanomedicine.

Extravasation is the first step for nanomedicines in circulation to reach targeted solid tumors. Traditional nanomedicines have been designed to extravasate into tumor interstitium through the interendothelial gaps previously assumed rich in tumor blood vessels, i.e., the enhanced permeability and retention (EPR) effect. While the EPR effect has been validated in animal xenograft tumor models, accumulating evidence implies that the EPR effect is very limited and highly heterogeneous in human tumors, leading to highly unpredictable and inefficient extravasation and thus limited therapeutic efficacy of nanomedicines, including those approved in clinics. Enabling EPR-independent extravasation is the key to develop new generation of nanomedicine with enhanced efficacy. Transcytosis of tumor endothelial cells can confer nanomedicines to actively extravasate into solid tumors without relying on the EPR effect. Here, we review and prospectthe development of transcytosis-inducing nanomedicines, in hope of providing instructive insights for design of nanomedicines that can undergo selective transcellular transport across tumor endothelial cells, and thus inspiring the development of next-generation nanomedicines for clinical translation.

A ROS-responsive synergistic delivery system for combined immunotherapy and chemotherapy.

Immune checkpoint blockade (ICB) therapies that target programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway are currently used for the treatment of various cancer types. However, low response rates of ICB remain the major issue and limit their applications in clinic. Here, we developed a ROS-responsive synergistic delivery system (pep-PAPM@PTX) by integrating physically-encapsulated paclitaxel (PTX) and surface-modified anti-PD-L1 peptide (pep) for combined chemotherapy and ICB therapy. Pep-PAPM@PTX could bind the cell surface PD-L1 and drive its recycling to lysosomal degradation, thus reverting PTX-induced PD-L1 upregulation and downregulating PD-L1 expression. As a result, pep-PAPM@PTX significantly promoted T cell infiltration and increased tumor immunoactivating factors, synergizing PTX chemotherapy to achieve enhanced anticancer potency in a triple-negative breast cancer (TNBC) model.