Cancer immunotherapy has revolutionized oncology by harnessing the immune system to eliminate malignant cells, yet its efficacy remains constrained by insufficient antigen presentation, limited T cell infiltration, and the immunosuppressive tumor microenvironment (TME). Nanotechnology provides strategies to address these barriers by enabling the precise delivery of antigens, adjuvants, cytokines, checkpoint inhibitors, and nucleic acids, while protecting labile cargos and allowing for controlled release. Beyond serving as carriers, nanoparticles can regulate antitumor immunity by enhancing antigen presentation, promoting T cell priming and infiltration, and remodeling the TME. This review outlines key physiological barriers to in vivo nanoparticle delivery and the corresponding engineering optimization strategies, and systematically summarizes representative advances in using nanomaterials to enhance antigen presentation, promote T cell priming and intratumoral infiltration, and remodel the tumor microenvironment. We further discuss major translational limitations, including heterogeneous tumor accumulation, intracellular trafficking bottlenecks, safety considerations, and manufacturing consistency, and finally highlight the realizable potential of nano-immunotherapy to improve both the efficacy and specificity of cancer immunotherapy.

Glioblastoma(GBM) is the most common malignant brain tumor. Although current treatment strategies, including surgery, chemotherapy, and radiotherapy, have achieved clinical effects and prolonged the survival of patients, the gradual development of resistance against current therapies has led to a high recurrence rate and treatment failure. Mechanisms underlying the development of resistance involve multiple factors, including drug efflux, DNA damage repair, glioma stem cells, and a hypoxic tumor environment, which are usually correlative and promote each other. As many potential therapeutic targets have been discovered, combination therapy that regulates multiple resistance-related molecule pathways is considered an attractive strategy. In recent years, nanomedicine has revolutionized cancer therapies with optimized accumulation, penetration, internalization, and controlled release. Blood-brain barrier(BBB) penetration efficiency is also significantly improved through modifying ligands on nanomedicine and interacting with the receptors or transporters on the BBB. Moreover, different drugs for combination therapy usually process different pharmacokinetics and biodistribution, which can be further optimized with drug delivery systems to maximize the therapeutic efficiency of combination therapies. Herein the current achievements in nanomedicine-based combination therapy for GBM are discussed. This review aimed to provide a broader understanding of resistance mechanisms and nanomedicine-based combination therapies for future research on GBM treatment.

Nano-drug delivery systems (nanoDDS) have been extensively investigated clinically to improve the therapeutic effect of anti-cancer drugs. However, the complicated synthesis during the preparation as well as the potential drug leakage during transportation has greatly limited their general application. In this work, a calixarene-integrated nanoDDS (CanD) that achieves tumor-targeted delivery and tracking of anti-cancer drugs in vivo is presented. The hypoxia-responsive calixarene (SAC4A) exhibits high binding affinity to a series of anti-cancer drugs and rhodamine B (RhB) under normoxic condition while decreasing the binding affinity under hypoxic condition, which leads to the drug release and fluorescence recovery simultaneously. Furthermore, the hypoxia-responsiveness of SAC4A conveys CanD with tumor-targeting ability, resulting in the enrichment of the drug in tumors and enhancement in tumor suppression in mice. Moreover, CanD could become a general platform allowing the delivery of a wide scope of anti-cancer drugs that have strong host-guest interaction with SAC4A.