Abstract: Described herein are methods of treating cancer by inducing favorable effects on tumor microenvironment (e.g., including macrophage polarization, cytokine profile, and/or immunophenotype) via administration of nanoparticles (e.g., silica-based ultra-small nanoparticles and nanoparticle conjugates such as nanoparticle drug conjugates). In certain embodiments, the methods may be used in concert with, or as part of, checkpoint inhibition therapy (e.g., anti-PD1) or radiotherapy, or a combination of both radiotherapy and checkpoint inhibitor therapy.