Photothermal and immunotherapeutic potentials of hyaluronic acid functionalized iron oxide nanoparticles with desirable tumor-associated macrophage reprogramming and T-cell Infiltrations to mitigate tumor recurrence.

Nanoscale photothermal therapy (PTT) of cancer is a promising strategy that can recruit tumor-associated antigens (TAAs) and alter the tumor microenvironment (TME). However, PTT, characterized by transient hypoxia and nonuniform heat distribution is often prompts the re-establishment of immunosuppressive TME implicated in tumor recurrence. This study aimed to complement PTT with immunomodulation to impart efficient hyperthermia and mitigate tumor recurrence. Thus, we prepared hyaluronic acid functionalized iron oxide nanoparticles (HA-IONPs), which demonstrated marked colloidal stability with desirable photothermal conversion efficiency pertinent to PTT. Interestingly, the HA-IONPs-mediated PTT had an appreciable cancer cell killing effect and nearly 4-fold pronounced M2/M1 reprogramming ability. They were more effective in preventing tumor relapse in CT-26 tumor-bearing mice compared to IONPs combined with the anti-PD-1 agent. HA-IONPs augmented with PTT (55 °C) propelled durable TAA release and cytotoxic T-cell infiltration through sustained disruption of the immunosuppressive TME, leading to a durable tumor growth inhibition (TGI) effect. Our innovative multimodal strategy, which combines hyperthermia and TAM reprogramming towards proinflammatory M1 phenotype, holds the promise not only for inhibiting the growth of tumors but also to mitigate relapse emanating from residual tumors, and thus, can be considered for further research and development.