Tumor-infiltrating lymphocytes (TILs) are key components of the tumor microenvironment (TME) and serve as prognostic markers for breast cancer. Patients with high TIL infiltration generally experience better clinical outcomes and extended survival compared to those with low TIL infiltration. However, as the TME is highly complex and TIL subtypes perform distinct biological functions, TILs may only provide an approximate indication of tumor immune status, potentially leading to biased prognostic results. Therefore, we reviewed the interactions between immune-infiltrating subtypes and tumor cells throughout the entire TME. By examining the antitumor or protumor effects of each TIL subtype, we aimed to better characterize the tumor immune landscape, offering more accurate and comprehensive insights for guiding triple-negative breast cancer (TNBC) treatment. In addition, this approach could lead to the development of new therapeutic targets, enabling tailored treatment strategies and precision medicine. Accumulating evidence suggests that the intestinal microbiome and its metabolites influence antitumor responses by modulating innate and adaptive immunity, with specific bacteria potentially serving as biomarkers for predicting clinical responses. Various studies have identified microorganisms in breast tissue, previously considered sterile, revealing differences in breast microbial composition between patients with breast cancer and controls, as well as associations between specific breast microorganisms and clinicopathologic features, including immune correlations. The aim of this review was to provide a more comprehensive set of prognostic markers for TNBC and to tap into potential-specific therapeutic targets.

Engagement of programmed death-ligand 1 (PD-L1) on tumor cells with its receptor PD-1 on immune cells can transmit an inhibitory signal to induce immune evasion. Although the immune checkpoint inhibitor PD-L1 antibody has shown antitumor capability in clinical treatment, its wide clinical application still faces several side effects and individual selectivity. In our research, we utilized the Clustered Regularly Interspaced Short Palindromic Repeats interference (CRISPRi) system to suppress PD-L1 expression on breast cancer cells (4T1) and combined it with epigenetic inhibitor azacytidine (AZA) for enhanced cancer immunotherapy. Reactive oxygen species (ROS)-responsive poly(β-amino ester) (PBAE)-S-AZA cationic polymeric prodrug was fabricated, which could complex with CRISPRi plasmids to form the composite polyplexes via electrostatic interaction. The composite polyplexes could be taken up by tumor cells with high efficiency, followed by plasmid release with the cooperation of PBAE. The CRISPRi plasmids could lead to PD-L1 downregulation in tumor cells, leading to obvious relief of immune checkpoint blockade. In the meantime, the epigenetic inhibitor AZA was also released from the polyplexes due to the high intracellular ROS level, thereby enhancing the efficacy of immunotherapy via elevating MHC class I expression, enhancing antigen presentation, and inducing dendritic cell (DC) maturation. The ROS-responsive polyplexes helped to realize the combination of genome editing, immunotherapy, and epigenetic regulation. It will provide an effective platform for promoting antitumor treatment and precision medicine.

Plant-derived exosome-like nanoparticles (PELNs), a subset of extracellular vesicle (EV) secreted by plant cells, have emerged as revolutionary biomaterial with broad applications in biomedicine, agriculture, and nanotechnology. Structurally, PELNs feature a phospholipid bilayer homologous to plant cell membranes, encapsulating bioactive components such as proteins, nucleic acids, lipids, and secondary metabolites. The native structure of PELNs endows them with enhanced bioavailability, reduced immunogenicity, and improved barrier penetration for precise tissue delivery. Recent studies highlight the cross-kingdom therapeutic potential of PELNs in mammals, including antitumor, anti-inflammatory, tissue repair, immunomodulation and so on. This review comprehensively summarized recent advancements in PELN research, including innovative isolation techniques, molecular characterization, their roles in drug delivery and disease therapy. We also discussed challenges in standardization, scalability, and regulatory frameworks which could provide future perspectives for translating PELNs into clinical and industrial applications.

Plant-derived exosome-like nanoparticles (PELNs), a subset of extracellular vesicle (EV) secreted by plant cells, have emerged as revolutionary biomaterial with broad applications in biomedicine, agriculture, and nanotechnology. Structurally, PELNs feature with phospholipid bilayer homologous to plant cell membranes, encapsulating bioactive components such as proteins, nucleic acids, lipids, and secondary metabolites. The native structure of PELNs endows them with enhanced bioavailability, reduced immunogenicity, and improved barrier penetration for precise tissue delivery. Recent researches highlight the cross-kingdom therapeutic potential of PELNs in mammals, including antitumor, anti-inflammatory, tissue repair, immunomodulation and so on. This review comprehensively summarized recent advancements in PELNs researches, including innovative isolation techniques, molecular characterization, their roles in drug delivery and disease therapy. We also discussed challenges in standardization, scalability, and regulatory frameworks which could provide future perspectives for translating PELNs into clinical and industrial applications.

Background/Objectives: Immune checkpoints are critical regulatory pathways that maintain peripheral tolerance and prevent autoimmunity. Among these, the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis serves as a major inhibitory pathway that terminates T cell responses. While protein-based checkpoint blockade (ICB) targeting this axis has revolutionized clinical cancer therapy, its clinical efficacy is frequently limited by low response rates, immune-related adverse events (irAEs), and the emergence of adaptive resistance. To break through these bottlenecks, genetic interruption has emerged as a high-precision alternative to modulate the PD-1/PD-L1 pathway at the nucleotide level. Methods: A comprehensive systematic review of literature was performed across major databases (PubMed, Web of Science), with a focus on high quality studies published up to 2026. Results: Direct genomic disruption via CRISPR/Cas9 and post-transcriptional silencing through RNA interference can effectively neutralize inhibitory signaling at its source. Recent advances demonstrate that targeting upstream regulatory nodes—including metabolic checkpoints (e.g., lactate metabolism) and biophysical mechanisms (e.g., liquid–liquid phase separation)—provides superior transcriptional control over PD-L1. Furthermore, engineering CAR-T cells with multiplex gene editing (e.g., TCR/B2M/PD-1 knockout) or localized scFv secretion significantly enhances antitumor potency while reducing systemic toxicity. Innovations in organ-targeted lipid nanoparticles and stimuli-responsive biomimetic carriers further address the delivery barriers in solid tumors. Conclusions: Gene therapy provides a high-precision platform for PD-1/PD-L1 modulation, offering a viable strategy to overcome adaptive resistance. Future clinical application depends on the refinement of safer editing tools, such as base editing, and the standardization of intelligent delivery systems to ensure controllable and scalable cancer immunotherapy.

Background: Photothermal therapy (PTT), a highly efficient and controllable method with minimal drug resistance, transforms near-infrared (NIR) radiation into heat. This process exerts antibacterial effects, aids in tissue repair, and promotes healing. Methods: Our study presented a novel kind of composite wound dressing that incorporated an adhesive conductive hydrogel (PTP) combined with a piezoelectric film (P/M) for NIR- responsive applications. The inherent adhesiveness of the hydrogel ensured robust anchoring of the piezoelectric film to both hydrogel matrix and wound site. Its conductivity enabled synergistic endogenous electrical stimulation with the piezoelectric film, while also serving as therapeutic layer to augment hemostasis, analgesia, and antibacterial activity. Results: The hydrogel’s capacity for moisture retention and exudate absorption sustained optimal wound environment, thereby supporting debridement and recovery. Furthermore, the P/M film possessed excellent photothermal properties and transferred heat to the hydrogel through heat conduction to enhance antibacterial activity and promote wound healing. The in vitro and in vivo experiments confirmed that the composite dressing exhibited strong promotion effect on wound healing under NIR irradiation. Conclusions: In summary, our research provided a new strategy for developing advanced piezoelectric biomaterials with great clinical potential for wound healing.