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.