ConspectusImmunotherapy has transformed the field of oncology and patient care. By leveraging the immune system of the host, immunostimulatory compounds exert a durable, personalized response against the patient's own tumor. Despite the clinical success, the overall response rate from current therapies (e.g., immune checkpoint inhibitors) remains low (∼20%) because tumors develop multiple resistance pathways at molecular, cellular, and microenvironmental levels. Unlike other oncologic therapies, harnessing antitumor immunity requires precise activation of a complex immunological system with multiple levels of regulation over its function. This requires the ability to exert control over immune cells in both intracellular compartments and various extracellular sites, such as the tumor microenvironment, in a spatiotemporally coordinated fashion.The immune system has evolved to sense and respond to nano- and microparticulates (e.g., viruses, bacteria) as foreign pathogens. Through the versatile control of composition, size, shape, and surface properties of nanoparticles, nano-immune-engineering approaches are uniquely positioned to mount appropriate immune responses against cancer. This Account highlights the development and implementation of ultra-pH-sensitive (UPS) nanoparticles in cancer immunotherapy with an emphasis on nanoscale cooperativity. Nanocooperativity has been manifested in many biological systems and processes (e.g., protein allostery, biomolecular condensation), where the system can acquire emergent properties distinct from the sum of individual parts acting in isolation.Using UPS nanoparticles as an example, we illustrate how all-or-nothing protonation cooperativity during micelle assembly/disassembly can be leveraged to augment the cancer-immunity cycle toward antitumor immunity. The cooperativity behavior enables instant and pH-triggered payload release and dose accumulation in acidic sites (e.g., endocytic organelles of antigen presenting cells, tumor microenvironment), intercepting specific immunological and tumor pathophysiological processes for therapy. These efforts include T cell activation in lymph nodes by coordinating cytosolic delivery of tumor antigens to dendritic cells with simultaneous activation of stimulator of interferon genes (STING), or tumor-targeted delivery of acidotic inhibitors to reprogram the tumor microenvironment and overcome T cell retardation. Each treatment strategy represents a nodal intervention in the cancer-immunity cycle, featuring the versatility of UPS nanoparticles. Overall, this Account aims to highlight nanoimmunology, an emerging cross field that exploits nanotechnology's unique synergy with immunology through nano-immune-engineering, for advancing cancer immunotherapy.
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