Advances in improving cancer immunotherapy with nanotechnology: from smart nanoparticles to synergistic combination strategies

Abstract Cancer immunotherapy has substantially advanced cancer treatment, achieving durable responses in select malignancies. However, its widespread application is limited by significant challenges: low efficacy in many solid tumors, severe side effects, and immune evasion facilitated by the tumor microenvironment (TME). Nanotechnology offers a promising approach to address these obstacles. By employing nanoparticles (NPs), we can precisely deliver therapeutics to tumor sites, ensure controlled release to minimize side effects, and amplify the immune response, thereby substantially boosting the effectiveness of immunotherapy. This review comprehensively highlights the latest advancements in using nanotechnology to enhance cancer immunotherapy. This paper details various applications of nanotech in this field. It discusses smart nanoparticles that respond to TME signals to release drugs (e.g., checkpoint inhibitors) directly at the tumor, reducing systemic side effects and activating T-cells. We also explore how nanovaccines, which co-deliver tumor markers and immune boosters, can induce antigen-specific immune responses. Furthermore, mRNA-loaded nanoparticles can directly modify CAR T-cells inside the body, simplifying treatment and increasing efficacy. Strategies like using PLGA NPs to deliver immune enhancers such as IL-2 are also presented, which activate immune cells while minimizing systemic issues. The review also explains how nanoparticles can re-engineer the immunosuppressive TME to create an environment more conducive to immune action. We also emphasize that nanotechnology-enhanced adoptive therapies, particularly cytokine-induced killer (CIK) cell immunotherapy, hold great potential to improve tumor targeting, treatment persistence durability, and overall anticancer efficacy. Collectively, we highlight synergistic effects achieved by combining nanoparticles with other treatments like chemotherapy, radiation, photothermal/photodynamic therapy, and more, which can turn hard-to-treat tumors into susceptible targets. The integration of nanotechnology and immunotherapy holds the potential to meaningfully advance future cancer therapy.