Immunotherapeutic Implications of Toll-like Receptors Activation in Tumor Microenvironment

Abstract

Toll-like receptors (TLRs) play an important role between innate and adaptive immunity as one of the pattern recognition receptors (PRRs). Both immune cells and tumor cells express TLRs, and the same TLR molecule is expressed in different cells with different roles. TLR activation in the tumor microenvironment mostly has a dual role in tumor progression during chronic inflammation. Clinically, the therapeutic efficacy of most cancer immunotherapy strategies is restricted by the suppressive immune infiltrative environment within the tumor. Therefore, activation of TLRs in innate immune cells has the potential to eradicate tumors lacking T-cell infiltration. TLR agonists have served as important immunomodulators of cancer immunotherapy through immune responses and reprogramming the tumor suppressive microenvironment. Meanwhile, considering the complex interaction of TLRs with the tumor microenvironment, a combined approach of cancer immunotherapy and nanotechnology has been adopted to improve cancer immunotherapy not only by combining multiple drug combinations, but also by targeting the tumor microenvironment using nanoparticles. Many clinical trials are underway to improve antitumor activity through combination with other immunotherapies. In this review, we provide a comprehensive and detailed overview of the immunotherapeutic implications of TLRs activation in tumor microenvironment, highlighting its great potential to be an important tool for cancer immunotherapy.

Epstein-Barr virus suppresses N6-methyladenosine modification of TLR9 to promote immune evasion

“…TLR9 agonist CpG ODN has been recognized as a promising adjuvant for cancer vaccines. It enhances the antitumor effects of T cells, shifting the immune response toward a Th1 phenotype ( 56 , 57 ). We further explored whether STM2457 could influence TLR9 function in antitumor immunity.…”

Seasonal influenza vaccines differentially activate and modulate toll-like receptor expression within the tumor microenvironment

“…TLR4 and TLR9 were shown to be the most responsive to the adjuvanted vaccine, AdjFluVx. Previous research has linked TLR4 and TLR9 activation to cancer growth in a variety of situations ( 30 – 32 ). As a result, our previously documented maintenance of tumor development following AdjFluVx treatment could be attributed to TLR4 and TLR9 activation, supporting an immunosuppressed tumor microenvironment.…”

“…TLR7 signaling may also activate dendritic cells, boosting tumor antigen presentation and promoting tumor-targeting CD8+ T cell responses. TLRs are expressed on both immune and tumor cells in the TME and play a dual role, triggering both anti-tumor (innate and adaptive immunity) and pro-tumor (cell proliferation, migration, invasion, and cancer stem cell maintenance), and have been linked to a variety of cancers including glioblastoma ( 31 ), breast cancer, melanoma, and brain tumors ( 32 ). TLR7 has been targeted as a potential therapeutic for hepatocellular carcinoma ( 33 ).…”

Small-molecule agents for cancer immunotherapy

“…Cell surface TLRs can be targeted by small molecules and antibodies whereas the intracellular nucleic-acid sensing TLRs could be targeted by modified oligonucleotides. To date, agonists for several TLRs, including TLR3, TLR4, TLR7, TLR8, and TLR9, have been tested clinically either alone or in combination with other therapies to strengthen the immune system in cancer therapy 24 , 27 , 28 .…”