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.

Malignant melanoma is a devastating skin cancer due to its severe drug resistance and prompt metastasis. Piperlongumine is an anti-inflammation and tumor-suppressing natural product with defined structure. While numerous studies revealed exceptional inhibitory effects of piperlongumine on several carcinomas, few investigations were performed on melanoma. Therefore, the present study investigated the anti-tumor effects of piperlongumine on human melanoma cells in vitro, and explored the mechanisms of action. Results from cytotoxicity and proliferation studies demonstrated that piperlongumine inhibited cell growth in melanoma cell lines A375, A875, and B16-F10 in a dose- and time-dependent manner. Flow cytometric analysis showed that piperlongumine obstructed cell cycle progression at G2/M phase and induced apoptosis in A375 cells. Mechanistic investigations illustrated that piperlongumine promoted reactive oxygen species production and decreased mitochondrial membrane potential. In addition, piperlongumine was reported to interfere with the expression of p21, p27, cleaved caspases-3, Bax, Bcl-2, and p-Jun N-terminal kinase (JNK), which are typical regulators associated with cell proliferation, intrinsic apoptosis, and JNKs pathway. Taken together, these results strongly suggested that piperlongumine inhibits cell growth and induces apoptosis in human melanoma cells via ROS mediated mitochondria disruption and JNKs pathway, and piperlongumine may exert promising potential for patients suffering from malignant melanoma.

Tumour poses tremendous challenges to mankind. In various tumours, matrix metalloproteases (MMPs) are ubiquitously over expressed and participate throughout the process of tumour development. MMPs are commonly used as internal stimuli, and MMPs-responsive nanomaterials are classified into three categories according to the drug delivery process: administration and distribution to tumour, intratumoural distribution and cell internalisation, and specific drug release. First, MMPs-sensitive polyethylene glycol (PEG) de-shielding and activatable cell penetrating peptides were developed to improve the blood circulation time of drug delivery systems, thereby, enhancing tumour or stroma cells recognition and penetration. Following tumour recognition, the MMPs-sensitive and size- or morphology-changeable nanoparticles (NPs) could highly accumulate and penetrate into tumour. Lastly, several MMPs-sensitive drug release strategies were feasible for both small molecule drugs and macromolecule drugs. In conclusion, recent novel advances of MMPs-responsive nanomaterials in tumour targeting diagnosis and treatment were highlighted in this review.