Combinatorial
methods to repolarize tumor-associated macrophages
from anti-inflammatory to pro-inflammatory phenotypes offer a promising
route for cancer immunotherapy. However, most studies examine biochemical
combinations alone. Therefore, we studied simultaneous chemical and
mechanical stimuli as orthogonal cues for enhanced immunomodulation.
We engineered the surfaces of hydrophobically functionalized mesoporous
silica nanoparticles (F108-hMSNs) to encapsulate the immunomodulator
resiquimod and kill cancer cells through high-intensity focused ultrasound
(HIFU)-mediated inertial cavitation, releasing damage-associated molecular
patterns (DAMPs) for prolonged macrophage stimulation. The HIFU doses
alone did not affect cells, but in combination with F108-hMSNs, achieved
significantly higher cancer cell death and DAMP generation. Inflammatory
markers (CD86, MHC II, iNOS) were upregulated in tumor-associated-like
macrophages treated with F108-hMSNs in the presence of HIFU and experienced
the greatest inflammatory phenotypic shift of all conditions tested.
This work suggests that chemical and mechanical activation facilitated
by engineered nanoparticles offer a promising treatment against immunologically
cold tumors.