Recent advances in tumor microenvironment-targeted nanomedicine delivery approaches to overcome limitations of immune checkpoint blockade-based immunotherapy.

Cancer immunotherapy has revolutionized the standard of care for solid tumors in multiple disease sites. In light of this, immune checkpoint blockade, directly interfering with various immunosuppressive mechanisms in tumor sites, has been actively studied. Inhibitors of cytotoxic T-lymphocyte-associated protein 4 (CTLA 4) and programmed cell death 1 receptor (PD-1) / programmed cell death receptor ligand 1 (PD-L1) could successfully increase survival rate in patients with advanced cancers including melanoma and non-small cell lung cancer, leading to increased survival and different patterns of response including durable response and pseudo-progression. Despite continued development of the immune checkpoint blockades, however, fairly low overall response rate (ORR) levels have been reported for patients with various types of cancer. Fewer than 13% of patients with cancer were reported to respond to immune checkpoint blockades and some patients were diagnosed with severe immune-related adverse events (irAEs). The tumor microenvironment, controlled via various components and mediators, is regarded as the primary cause responsible for failure of immune checkpoint blockades in clinical investigations. In fact, there has been a clinical report that epidermal growth factor receptor (EGFR) inhibition in tumor microenvironment enhanced ORR of PD-1 inhibitors for 29.7% in EGFR-mutated non-small-cell lung carcinoma (NSCLC) patients. Therefore, to enhance the effectiveness and reduce adverse effects of immune checkpoint blockades, the majority of studies have focused on targeting and suppressing the immunosuppressive characteristics of the tumor microenvironment. Herein, we review the components and mediators of tumor microenvironment responsible for failure of immune checkpoint blockades and introduce the recent approaches of tumor microenvironment component-targeted nanomedicine delivery capable of enhancing the efficacy of immune checkpoint blockades. Understanding the active targeting candidates of tumor microenvironment components and the associated treatment strategies could offer insights into the development of combination therapeutics boosting immune checkpoint blockades for clinical applications.