Nano-Immunoconjugates in Immune Checkpoint Blockade: A Dual Approach to Precision Immunotherapy and Real-Time Imaging.

Immune checkpoint blockade (ICB) therapies have revolutionized the treatment of cancer by harnessing the body's immune system to recognize and eradicate tumor cells. Despite clinical successes, the systemic administration of checkpoint inhibitors remains hampered by limited tumor targeting, immune-related adverse events (irAEs), and the absence of real-time monitoring to guide therapeutic responses. The emergence of nano-immunoconjugates-nanoscale platforms functionalized with immune checkpoint inhibitors (ICIs) and imaging agents-represents a next-generation strategy to address these challenges. By enabling site-specific delivery and integrating molecular imaging modalities, such as positron emission tomography (PET), magnetic resonance imaging (MRI), near-infrared fluorescence (NIRF), and photoacoustic imaging, nano-immunoconjugates, offer dual benefits: enhanced immunotherapeutic precision and non-invasive monitoring of drug biodistribution and immune engagement. Various nanocarrier systems, including liposomes, polymeric nanoparticles, dendrimers, gold nanoparticles, and exosomes, have been engineered to deliver programmed death-1 (PD-1)/PD-L1 and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) inhibitors with superior targeting specificity, stimuli-responsive release, and imaging compatibility. Preclinical studies have demonstrated improved T-cell activation, reduced tumor burden, and favorable biodistribution profiles, whereas early clinical investigations highlight their translational potential. However, challenges, such as immunogenicity, regulatory complexity, and scalability persist. This review systematically explores the mechanistic foundations, nanoformulation strategies, integrated imaging approaches, tumor microenvironment (TME) navigation, and clinical outlook of nano-immunoconjugates.