Nanoparticle accumulation in liver may induce resistance to immune checkpoint blockade therapy

Despite immune checkpoint blockade (ICB) therapy has transformed cancer treatment, only 20.2% of these patients achieved a response. Understanding resistance mechanisms to ICB is important for the treatment of a wider population. In this work, we occasionally found that the silica nanoparticles (SiO₂ NPs) accumulated in the liver can induce resistance to following ICB therapy to a subcutaneous tumor in mice. By analysis of T cells frequency, we uncovered that SiO₂ NPs in the liver resulted in a siphoning of T cells from circulation to the liver by produced chemokines. In addition, liver immunosuppressive cells further inhibit the function and induce apoptosis of recruited T cells, leading to a systemic loss and reduced tumor infiltration of T cells, which contributes to poor responses to ICB therapy. However, such effect is not observed in poly(lactic-co-glycolic acid) (PLGA) NPs treated mice under the same conditions, likely due to their much lower immunogenicity in perturbing the liver immune microenvironment, indicating that cancer is not a local disease but an ecosystem that is linked to the distal environment. We further provide a new mechanism insight into ICB resistance induced by liver accumulation of nanoparticles.