Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies, on account of its good safety and long-term memory ability. Discouragingly, low patient response rates and potential immune-related side effects make it rather challenging to literally bring immunotherapy from bench to bedside. However, it has become evident that, although the immunosuppressive tumor microenvironment (TME) plays a pivotal role in facilitating tumor progression and metastasis, it also provides various potential targets for remodeling the immunosuppressive TME, which can consequently bolster the effectiveness of antitumor response and tumor suppression. Additionally, the particular characteristics of TME, in turn, can be exploited as avenues for designing diverse precise targeting nanomedicines. In general, it is of urgent necessity to deliver nanomedicines for remodeling the immunosuppressive TME, thus improving the therapeutic outcomes and clinical translation prospects of immunotherapy. Herein, we will illustrate several formation mechanisms of immunosuppressive TME. More importantly, a variety of strategies concerning remodeling immunosuppressive TME and strengthening patients' immune systems, will be reviewed. Ultimately, we will discuss the existing obstacles and future perspectives in the development of antitumor immunotherapy. Hopefully, the thriving bloom of immunotherapy will bring vibrancy to further exploration of comprehensive cancer treatment.

Photodynamic therapy (PDT) is a new therapeutic strategy for hypertrophic scars (HS), but it is limited by low drug utilization. Transdermal delivery based on nanoethosomes (ES) has attracted considerable attention as a potential clinical strategy in PDT treating HS. However, free ES are unsatisfactory due to their instability and non-targeting, which causes non-effective delivery and low drug utilization. Herein, 5-aminolevulinic acid (ALA)-loaded ES (ES-ALA) embedded in hyaluronic acid (HA) meshes (HA/ES-ALA), a novel synergistic transdermal delivery nanogel, are developed for enhancing PDT of HS. HA/ES-ALA has a unique structure and property to protect unilaminar ES-ALA with HA meshes and actively target hypertrophic scar fibroblasts (HSFs) with HA receptors. Both in vitro and in vivo experiments demonstrate that HA/ES-ALA has a remarkable transdermal delivery ability with penetrating channels and a membrane-fusion mechanism. Meanwhile, the synergistic delivery mechanism is visually characterized as three stages: synergistic penetration, targeting aggregation and transmembrane delivery. With the synergistic effect, HA/ES-ALA can realize a targeted transdermal delivery, and significantly improve ALA utilization and enhance PDT efficacy. The results demonstrate an effective transdermal delivery route to enhance therapy for HS as well as other skin diseases.

Photodynamic therapy (PDT) is an emerging therapeutic strategy for hypertrophic scars (HS), which is heavily dependent on reactive oxygen species (ROS) generation. However, the unsatisfactory delivery and excitation of 5-aminolevulinic acid (ALA, a commercial photosensitizer in dermatology) result in an insufficient ROS generation, and thus limit the clinical application of PDT treating HS (HS-PDT). Consequently, sophisticated transdermal co-delivery nanoethosomes (named A/A-ES) with ALA and Au nanotriangles (AuNTs) in cores are prepared via an in-situ seed-mediated growth method, and then applied to improve HS-PDT through localized surface plasmon resonance (LSPR)-enhanced ROS generation. A/A-ES display a satisfactory performance in co-delivery in HS tissue with sufficient protoporphyrin IX production and LSPR effect in cytoplasm, which is beneficial for ALA excitation as well as ROS generation. In vitro/vivo studies reveal that A/A-ES significantly improve HS-PDT in promoting to fibroblast apoptosis and collagen remodeling through LSPR-enhanced ROS generation. Therefore, this study provides a feasible strategy that integrates transdermal delivery and LSPR to enable the beneficial effects of HS-PDT through boosting the delivery and excitation of ALA.

Extracellular vesicles (EVs) are lipid membrane-bound vesicles involved in cell-cell communication, particularly in the context of cancer. Immunotherapy, a rapidly evolving field in oncology, is a type of cancer treatment relying on the body’s own immune system to fight mutated cancer cells. Recently, the significance of immunotherapeutic resistance has been increasingly acknowledged owing to the heightened prevalence of cancer and its commonly advanced stage upon diagnosis. However, the complexity and heterogeneity of tumor cells pose challenges to immunotherapy, and the role of EVs in immunotherapeutic resistance remains unclear. Recent studies focused on the role of EVs as heterogeneous groups of nanoparticles in intercellular communication, particularly within the tumor microenvironment (TME). EVs, which include exosomes, shed microvesicles, while apoptotic bodies carry a diverse range of molecular cargo, including proteins, nucleic acids, lipids, and other bioactive molecules. The complexity and versatility of EVs make them a fascinating area of study, with promising implications for the future of immunology and medicine. This brief review highlights the involvement of EVs in immunotherapeutic resistance (e.g., PD-L1 transfer, miRNA-mediated pathways) with a focus on their biogenesis, secretion, and functional roles in cancer, underscoring their potential as diagnostic and therapeutic tools.