Toll-Like Receptors Signaling in the Tumor Microenvironment

  • Kelly D. McCall
  • Maria Muccioli
  • Fabian BenenciaEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1223)


The involvement of inflammation in cancer progression is well-established. The immune system can play both tumor-promoting and -suppressive roles, and efforts to harness the immune system to help fight tumor growth are at the forefront of research. Of particular importance is the inflammatory profile at the site of the tumor, with respect to both the leukocyte population numbers, the phenotype of these cells, as well as the contribution of the tumor cells themselves. In this regard, the pro-inflammatory effects of pattern recognition receptor expression and activation in the tumor microenvironment have emerged as a relevant issue both for therapy and to understand tumor development.

Pattern recognition receptors (PRRs) were originally recognized as components of immune cells, particularly innate immune cells, as detectors of pathogens. PRR signaling in immune cells activates them, inducing robust antimicrobial responses. In particular, toll-like receptors (TLRs) constitute a family of membrane-bound PRRs which can recognize pathogen-associated molecular patterns (PAMPs) carried by bacteria, virus, and fungi. In addition, PRRs can recognize products generated by stressed cells or damaged tissues, namely damage-associated molecular patterns or DAMPS. Taking into account the role of the immune system in fighting tumors together with the presence of immune cells in the microenvironment of different types of tumors, strategies to activate immune cells via PRR ligands have been envisioned as an anticancer therapeutic approach.

In the last decades, it has been determined that PRRs are present and functional on nonimmune cells and that their activation in these cells contributes to the inflammation in the tumor microenvironment. Both tumor-promoting and antitumor effects have been observed when tumor cell PRRs are activated. This argues against nonspecific activation of PRR ligands in the tumor microenvironment as a therapeutic approach. Therefore, the use of PRR ligands for anticancer therapy might benefit from strategies that specifically deliver these ligands to immune cells, thus avoiding tumor cells in some settings. This review focuses on these aspects of TLR signaling in the tumor microenvironment.


Toll-like receptors (TLRs) Pathogen-associated molecular patterns (PAMPs) Damage-associated molecular patterns (DAMPs) Pathogen recognition receptors (PRRs) Inflammation Growth factors MDA5 RIG-I Cancer Tumor microenvironment Cancer therapy Inflammation Macrophages Dendritic cells Ismmunosuppression 



This work was supported in part by the NIH under Grant R15 CA137499-01 (FB), a startup fund from OU (FB), a Research and Scholarly Awards Committee grant (RP1206) from the Heritage College of Osteopathic Medicine, OU; and Ohio University-Baker Funds Award (FN1006078). Figures were created using the Library of Science and Medical Illustrations free resource (


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Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Kelly D. McCall
    • 1
    • 2
    • 3
  • Maria Muccioli
    • 4
  • Fabian Benencia
    • 2
    • 3
    • 4
    Email author
  1. 1.Department of Specialty Medicine, Heritage College of Osteopathic MedicineOhio UniversityAthensUSA
  2. 2.Molecular and Cellular Biology ProgramOhio UniversityAthensUSA
  3. 3.Diabetes InstituteOhio UniversityAthensUSA
  4. 4.Department of Biomedical Sciences, Heritage College of Osteopathic MedicineOhio UniversityAthensUSA

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