Dual and multi-immune activation strategies for emerging cancer immunotherapy

Cancer immunotherapy is revolutionizing clinical oncology and prosperously advanced by immune agonists that boost immune stimulation. In recent years, nano-agonists with tunable physicochemical properties have been developed to address the challenges faced by naked immune agonists, such as sub-optimal pharmacokinetics and off-target in vivo accumulation. Notably, due to the potential complementary or synergistic effects between immune agonists targeting distinct signaling pathways, nano-agonists that integrate dual or multiple immune activation modalities show promise in broadening the anti-tumor repertoire and have emerged as a significant topic in cancer immunotherapies. In addition to protecting payloads and facilitating their targeted accumulation, innovative nano-formulations can deliver combinations of immune adjuvant at optimized dosage ratios. To date, dual and multi-immune activation nano-agonists have been extensively explored, demonstrating promising pre-clinical performance in murine tumor models and significant potential for clinical translation. This review provides an overview of dual and multi-immune activation nano-strategies based on targeted signaling pathways and their performance in cancer immunotherapies and discusses the challenges and prospects for clinical translation.