Immune checkpoint inhibitors, like PD-1/PD-L1 blockers, have revolutionized cancer treatment in recent years. However, these therapies still face many problems, such as low objective response rates and drug resistance, making clinical treatment very difficult. Numerous studies have demonstrated that the heterogeneity of the tumor microenvironment (TME), including various subtypes such as “cold tumors”, “hot tumors”, and “immune-rejecting tumors”, as well as complex immunosuppressive mechanisms, is a major factor leading to resistance to immunotherapy. Chemotherapy and radiotherapy can aid in treatment by inducing immunogenic cell death, but they often lead to PD-L1 upregulation, which causes treatment effects to vary over time and space and reduces their efficacy. Given their excellent biocompatibility, drug delivery capacity, and responsiveness to environmental factors, nanomaterials offer a novel opportunity to address this challenge. This review explores sequential nanoregulation strategies based on different types of TME, describes how functionalized nanocarriers, such as stimulus-responsive polymers, liposomes, and biomimetic nanoparticles, can be used to detect changes in the microenvironment, like pH, enzymes, and reactive oxygen species, and to precisely deliver drugs when needed. This will allow researchers to target key points of immune activation, thereby blocking immune checkpoint signaling. These specific strategies, which include antigen release, immune system activation, and blocking interventions, not only offer new approaches for overcoming PD-L1 resistance but also shed light on the challenges and opportunities associated with applying these strategies in clinical practice.
