Overcoming resistance to anti-PD-L1 immunotherapy: mechanisms, combination strategies, and future directions

Cancer cells express high levels of programmed cell death-ligand 1 (PD-L1) to evade immune surveillance. PD-L1 interacts with PD-1 on T cells to make them non-functional. Thus, PD-L1 and PD-1 are pivotal targets in cancer immunotherapy. While anti-PD-1/PD-L1 therapies have offered renewed hope for many patients, their modest efficacy remains a critical concern. This underscores the urgent need to unravel the intricate mechanisms that govern both therapeutic responses as well as resistance to immunotherapy. This review explores the multifaceted nature of PD-L1, including factors that regulate its expression, tumor-immune interactions, and the resistance mechanisms associated with anti-PD-L1 immunotherapy. Several promising strategies have been explored to overcome these challenges, such as combination therapies, modulation of the tumor microenvironment, neoantigen targeting, and dynamic biomarker monitoring. Outcomes of these approaches, integrating advanced technologies like high-resolution imaging, machine learning, multi-omics profiling, and liquid biopsy for soluble PD-L1 detection emerge as a powerful means to refine patient stratification. Together, these innovations pave the way toward more precise and personalized immunotherapy, maximizing clinical benefits for cancer patients. Additionally, the evolving landscape of clinical trials involving anti-PD-1/PD-L1 monoclonal antibodies has been explored, emphasizing the integration of immune checkpoint therapies with chemotherapy, radiotherapy, targeted therapy, CAR-T, and metabolic immunotherapy to overcome resistance in refractory cancers. By embarking on these challenges and leveraging novel therapeutic strategies, this review intends to advance the understanding of more effective, personalized cancer immunotherapies, ultimately improving outcomes for a broader range of patients.