Reinforcing the Combinational Immuno-Oncotherapy of Switching “Cold” Tumor to “Hot” by Responsive Penetrating Nanogels

Abstract

Although immuno-oncotherapy in clinic has gained great success, the immunosuppressive tumor microenvironment (TME) existing in the "cold" tumor with insufficient and exhausted lymphocytes may result in a lower-than-expected therapeutic efficiency. Therefore, a properly designed synergistic strategy that can effectively turn the "cold" tumor to "hot" should be considered to improve the therapeutic effects of immuno-oncotherapy. Herein, TME-responsive penetrating nanogels (NGs) were developed, which can improve the delivery and penetration of the co-loaded resiquimod (R848) and green tea catechin (EGCG) in tumors by a nano-sized controlled releasing system of the soluble cyclodextrin-drug inclusion complex. Consequently, the NGs effectively promoted the maturation of dendritic cells, stimulated the cytotoxic T lymphocytes (CTLs), and decreased the PD-L1 expression in tumors. The combination of NGs with the OX40 agonist (αOX40) further synergistically enhanced the activation and infiltration of CTLs into the deep tumor and inhibited the suppression effects from the regulatory T cells (Tregs). As a result, an increased ratio of active CTLs to Tregs in tumors (20.66-fold) was achieved with a 91.56% tumor suppression effect, indicating a successful switch of "cold" tumors to "hot" for an immunologically beneficial TME with significantly improved anti-tumor immune therapeutics. This strategy could be tailored to other immuno-oncotherapeutic approaches to solve the urgent efficiency concerns of the checkpointbased treatment in clinic.

Applications of Magnetite Nanoparticles in Cancer Immunotherapies: Present Hallmarks and Future Perspectives

“…Besides macrophages and the innate immune cells, stimulating CTLs could be considered as another effective approach for improving the anti-tumor immune responses and was also widely studied (58). A solid tumor can be defined as "cold" or "hot", depending on the degree and localization of tumorinfiltrating CTLs and the immunological condition of the TME (59,60).…”

“…Meanwhile, the exhaustion of infiltrated CTLs can be induced by the immune suppressive checkpoints in TME, e.g., the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) or the cytotoxic T lymphocyte antigen-4 (CTLA-4), which hindered the development of anti-tumor specific CTLs responses (62). Conversely, a "hot" tumor exhibits a high accumulation and infiltration of non-exhausted CTLs, DCs, and natural killer cells (NKs), thus being an ideal target for immuno-oncotherapy (58,63). Thus, to improve the overall response rate (ORR) of the current immuno-oncotherapy, a growing number of MNP-based immunotherapeutic strategies aim at turning the "cold" tumors to "hot" by enhancing the number of infiltrating CTLs and modulation of immune checkpoint blockade (ICB) in TME (Figure 2).…”

Bioengineered nanogels for cancer immunotherapy

“…15d). 264 After reaching the TME, the breakage of the ketal in the nanogel released R848 and epigallocatechin gallate (EGCG), which enhanced the penetration of the drug in the tumour and stimulated the maturation of DCs. Further stimulation with an OX40 agonist (aOX40) not only promoted the activation and infiltration of CTL but also inactivated Treg by inhibiting the expression of the transcription factor FOXP3, reshaping the 'cold' tumours to 'hot' tumours.…”

Locally Injectable Hydrogels for Tumor Immunotherapy

“…The immunosuppressive tumor microenvironment (TME) can lead to an insufficient infiltration of effector lymphocytes and a depletion of function, greatly weakening the antitumor immune effect, prompting the tumor to become “cold” and making the tumor immunotherapy far less effective than expected [ 6 ]. Therefore, the design of a reasonable treatment strategy to effectively turn “cold” tumors into “hot” tumors using active effector lymphocytes is the key to improve the effect of antitumor immunotherapy [ 7 ]. An appropriate immunotherapy enables the immune system to regain an anticancer role in the TME, thereby controlling or even eliminating cancer cells.…”