The tumor microenvironment, immune response and the COC Protocol

The body’s own anti-tumor immune response can be a powerful weapon against cancer. Once mobilized it can target and destroy cancer cells very efficiently. New and developing immunotherapies seek to harness this ability. But tumors are also very good at recruiting the immune system for their own protection. Scientists are looking for ways to help improve the body’s immune system respond to cancer and help facilitate immunotherapy treatment activity.

Tumor Associated Macrophages (TAMs) are key immune cells which help to modulate the body’s own anti-tumor immune response. TAMs circulate in the region immediately around the tumor, called the tumor microenvironment. Once recruited by the tumor, TAMs can help to promote growth and spread of tumor cells. They can also help to stimulate the formation of new blood vessels (angiogenesis) to feed the tumor.

TAMs are generally thought to ‘polarize’ into anti-tumor M1-type or pro-tumor M2-type cells, depending on outside signals they receive. This is a growing field of research, and scientists are still working to understand just how and when TAMs can polarize to promote or inhibit cancer growth. However, there is emerging evidence that polarization of TAMs may in part be influenced by the metabolic state (i.e. nutrient availability) of the tumor microenvironment. In this way, TAMs and cancer cells may also be able to directly influence each other, depending on their own metabolic activity (Vitale et al, 2019).

In line with this, emerging evidence also suggests that the COC Protocol medications (which can help to influence cell metabolic activity), may help to beneficially modulate the anti-tumor activity of TAMs and other immune cells.

For example, a 2018 lab study found that metformin can ‘skew’ TAM polarization in the tumor microenvironment from pro-tumor M2 to anti-tumor M1. Metformin inhibited both tumor growth and angiogenesis in this study (Wang et al. 2018). Other studies suggest metformin may also boost other immune cell functions, potentially helping to increase abundance of (anti-cancer) tumor infiltrating lymphocytes, and enhancing the cancer cell-killing ability of  T-cells (Pereira et al 2018).

Mebendazole has also been shown to help initiate the TAM mediated anti-tumor immune response. In one study, gene expression profiling in mebendazole-treated breast cancer and leukemia cells showed that mebendazole strongly upregulated several genes related to activation of the anti-tumor M1 monocyte/macrophage (i.e. TAMs). A further lab study in colon cancer cells also showed that mebendazole’s tumor suppressive effect is intrinsically linked to monocyte/macrophage immune cell response (both studies reviewed in Guerini et al 2019).

Further reports suggest that statins and doxycycline can also have antitumor effects on TAM polarization and other immune cell functions. For example, in a study which analyzed samples from patients with lung cancer, statin use was associated with reduced levels of pro-tumor TAMs, and reduced tumor invasiveness (Dujaily et al. 2020). And in a mouse model of breast cancer, statin helped to improve anti-tumor T cell infiltration into tumors, and decrease the number of M2-type TAMs. Initiation of new cancerous lesions in these mice was also decreased (Mira et al. 2013). In a different study using a mouse model of breast cancer, doxycycline slowed tumor growth, and this effect was associated with changes in levels of cytokines and TAMs (Tang et al. 2017).


Important Notice

Purpose of this article

This article is an overview of some of the scientific and medical published literature concerning the medications which comprise the patented Care Oncology protocol. Care has been taken to select relevant articles supporting the off-label use of these medicines in a clinical setting for the adjunct treatment of cancer. This article does not purport to be a comprehensive review of all the evidence, nor does it capture all the potential side-effects of such treatment.

This article is for information purposes only and it does NOT constitute medical advice. The medicines discussed herein are available on prescription-only and should not be taken without consultation with your doctor or other professional healthcare provider. Care Oncology doctors will discuss the suitability of these medicines with you and will liaise with your doctor or oncologist to discuss their suitability for you.

You must NOT rely on the information in this article as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter you should consult your doctor or other professional healthcare provider. If you think you may be suffering from any medical condition you should seek immediate medical attention. You should never delay seeking medical advice, disregard medical advice, or discontinue medical treatment because of information contained in this article.


The copyright in this article is owned by Health Clinics USA Corp and its licensors.


The Care Oncology (“COC”) Protocol is protected by United States patent US9622982B2 and by various additional international patents.





Dujaily, Esraa Al, Juvenal Baena, Madhumita Das, Marco Sereno, Claire Smith, Tamihiro Kamata, Leah Officer, Catrin Pritchard, and John Le Quesne. 2020. “Reduced Pro-Tumourigenic Tumour-Associated Macrophages with Statin Use in Premalignant Human Lung Adenocarcinoma.” JNCI Cancer Spectrum.

Guerini, Andrea Emanuele, Luca Triggiani, Marta Maddalo, Marco Lorenzo Bonù, Francesco Frassine, Anna Baiguini, Alessandro Alghisi, et al. 2019. “Mebendazole as a Candidate for Drug Repurposing in Oncology: An Extensive Review of Current Literature.” Cancers 11 (9).

Jeong, Hoibin, Sehui Kim, Beom-Ju Hong, Chan-Ju Lee, Young-Eun Kim, Seoyeon Bok, Jung-Min Oh, et al. 2019. “Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis.” Cancer Research 79 (4): 795–806.

Mira, Emilia, Lorena Carmona-Rodríguez, Manuel Tardáguila, Iñigo Azcoitia, Alicia González-Martín, Luis Almonacid, Josefina Casas, Gemma Fabriás, and Santos Mañes. 2013. “A Lovastatin-Elicited Genetic Program Inhibits M2 Macrophage Polarization and Enhances T Cell Infiltration into Spontaneous Mouse Mammary Tumors.” Oncotarget 4 (12): 2288–2301.

Pereira, Melo, Low, de Castro, Braga, Almeida, Batista de Lima, Hiyane, Correa-Costa, Andrade-Oliveira, Origassa, Pereira, Kaech, Rodrigues, Olsen, Camara, 2018.  Metformin exerts antitumor activity via induction of multiple death pathways in tumor cells and activation of a protective immune response.”

Tang, Xiaoyun, Xianyan Wang, Yuan Y. Zhao, Jonathan M. Curtis, and David N. Brindley. 2017. “Doxycycline Attenuates Breast Cancer Related Inflammation by Decreasing Plasma Lysophosphatidate Concentrations and Inhibiting NF-ΚB Activation.” Molecular Cancer 16 (February).

Vitale, Ilio, Manic, Gwenola, Coussens, Lisa M, Kroemer, Guido, Galluzzi, Lorenzo. “Macrophages and Metabolism in the Tumor Microenvironment.” Cell Metab. 2019;30(1):36-50. https://doi:10.1016/j.cmet.2019.06.001.