Small-Molecule Modulators Targeting Toll-like Receptors for Potential Anticancer Therapeutics

Abstract

Toll-like receptors (TLRs) are key components of the innate immune system and serve as a crucial link between innate and acquired immunity. In addition to immune function, TLRs are involved in other important pathological processes, including tumorigenesis. TLRs have dual regulatory effects on tumor immunity by activating nuclear factor κ-B signaling pathways, which induce tumor immune evasion or enhance the antitumor immune response. Therefore, TLRs have become a popular target for cancer prevention and treatment, and TLR agonists and antagonists offer considerable potential for drug development. The TLR7 agonist imiquimod (1) has been approved by the U.S. Food and Drug Administration as a treatment for malignant skin cancer. Herein, the structure, signaling pathways, and function of the TLR family are summarized, and the structure−activity relationships associated with TLR selective and multitarget modulators and their potential application in tumor therapy are systematically discussed.

Recent advances in treating female genital human papillomavirus related neoplasms with topical imiquimod

“…Imiquimod, through its immunomodulatory action, also exerts essential antitumor effects, as supported by several in vitro and in vivo studies. By promoting IFN‐γ and IL‐12 and inhibiting IL‐4 and IL‐5, it polarizes the immune microenvironment to a Th1‐cytokine pattern, increasing the recruitment of T‐cells 39 . This immune microenvironment reshape was first reported by Sander et al, who documented that the treatment with imiquimod in a murine model immunized with E7 led to increased rejection of HPV 16 positive cells and to the shrinkage of E7 positive tumors, determined by the Th1 cells stimulating a delayed‐type hypersensitivity skin test reaction 40 .…”

Structural Optimization and Biological Evaluation of Isoxazolo[5,4-d]pyrimidines as Selective Toll-Like Receptor 7 Agonists

“…However, despite their high affinity, many of the small molecules developed face challenges in clinical development due to lack of efficacy and negative effects on the host immune response. Overall, the search for small-molecule TLR7 agonists with improved pharmacokinetic properties, reduced side effects, and increased therapeutic efficacy remains a significant challenge in this field. , …”

Therapeutic Potential of Methotrexate-Loaded Superparamagnetic Iron Oxide Nanoparticles Coated with Poly(lactic-co-glycolic acid) and Polyethylene Glycol against Breast Cancer: Development, Characterization, and Comprehensive In Vitro Investigation

“…Methotrexate sodium is an antineoplastic drug that inhibits dihydrofolate reductase, thus preventing the conversion from dihydrofolate to tetrahydrofolate . Methotrexate sodium is used to treat various cancers, such as breast cancer, lung cancer, head and neck cancer, and skin cancer . Apart from its original use as a cancer chemotherapeutic agent, it has been suggested for several other diseases, such as psoriasis, multiple sclerosis, Crohn’s disease, and rheumatoid arthritis.…”