Breaking Physical Barrier of Fibrotic Breast Cancer for Photodynamic Immunotherapy by Remodeling Tumor Extracellular Matrix and Reprogramming Cancer-Associated Fibroblasts.

Cancer-associated fibroblasts (CAFs) assist in breast cancer (BRCA) invasion and immune resistance by overproduction of extracellular matrix (ECM). Herein, we develop FPC@S, a photodynamic immunomodulator that targets the ECM, to improve the photodynamic immunotherapy for fibrotic BRCA. FPC@S combines a tumor ECM-targeting peptide, a photosensitizer (protoporphyrin IX) and an antifibrotic drug (SIS3). After anchoring to the ECM, FPC@S causes ECM remodeling and BRCA cell death by generating reactive oxygen species (ROS) in situ. Interestingly, the ROS-mediated ECM remodeling can normalize the tumor blood vessel to improve hypoxia and in turn facilitate more ROS production. Besides, upon the acidic tumor microenvironment, FPC@S will release SIS3 for reprograming CAFs to reduce their activity but not kill them, thus inhibiting fibrosis while preventing BRCA metastasis. The natural physical barrier formed by the dense ECM is consequently eliminated in fibrotic BRCA, allowing the drugs and immune cells to penetrate deep into tumors and have better efficacy. Furthermore, FPC@S can stimulate the immune system and effectively suppress primary, distant and metastatic tumors by combining with immune checkpoint blockade therapy. This study provides different insights for the development of fibrotic tumor targeted delivery systems and exploration of synergistic immunotherapeutic mechanisms against aggressive BRCA.

Recent Progress in Carrier-Free Nanomedicine for Tumor Phototherapy.

Safe and effective strategies are urgently needed to fight against the life-threatening diseases of various cancers. However, traditional therapeutic modalities, such as radiotherapy, chemotherapy and surgery, exhibit suboptimal efficacy for malignant tumors owing to the serious side effects, drug resistance and even relapse. Phototherapies, including photodynamic therapy (PDT) and photothermal therapy (PTT), are emerging therapeutic strategies for localized tumor inhibition, which can produce a large amount of reactive oxygen species (ROS) or elevate the temperature to initiate cell death by non-invasive irradiation. In consideration of the poor bioavailability of phototherapy agents (PTAs), lots of drug delivery systems have been developed to enhance the tumor targeted delivery. Nevertheless, the carriers of drug delivery systems inevitably bring biosafety concerns on account of their metabolism, degradation, and accumulation. Of note, carrier-free nanomedicine attracts great attention for clinical translation with synergistic antitumor effect, which is characterized by high drug loading, simplified synthetic method and good biocompatibility. In this review, the latest advances of phototherapy with various carrier-free nanomedicines are summarized, which may provide a new paradigm for the future development of nanomedicine and tumor precision therapy.