**Acknowledgements**

**4. Discussion**

72 Cancer Survivorship

burden and metastasis.

the efficient response to the peptide is imperative.

with different types of neoplasms [91, 112–116].

cell exhaustion or DC dysfunction.

**5. Conclusions**

The ability of the GK-1 peptide to increase survival, significantly to delay tumor growth, and to reduce metastasis is discussed in this review. Considering that the immune system plays a crucial role in the outcome of cancer, orchestrating the response that may lead either to the control or dissemination of tumors [8, 78, 104], understanding the mechanisms that underlie

It has been reported that the production of pro-inflammatory cytokines both by tumor and surrounding cells, along with the production of growth factors and chemokines, can promote the development of neoplasia by facilitating carcinogenesis programs, inducing a sustained cellular proliferative rate, inhibiting apoptosis and stimulating angiogenesis [105, 106]. As described above, GK-1 therapy contributed to decrease the levels of IL-4, IL-10, b-FGF, and GM-CSF; these chemoattractants, along with hypoxia, promote macrophage shift from a M1 to a M2 phenotype. M2-like tumor-associated macrophages (TAM) stimulate immunosuppression and increase blood vessel density, favoring angiogenesis. In a breast cancer model, lower CCL2 and CCL3 levels in the lungs of mice treated with GK-1 could be decreasing the migration of inflammatory monocytes such as MAM and MDSC, which promote metastasis [8, 13, 102, 107]. These changes in the microenvironment seem to contribute to control tumor

On the other hand, M1-like macrophages can contribute to tumor regression by recruiting cytotoxic CD8+ T (CTL) and NK cells [108–110]. In this regard, IL-12 induction by APCs could be contributing to the increase in the proliferation of CD8+ and CD4+ lymphocytes and the induction of a Th1 response, as previously reported [51, 52, 111]. Several studies have suggested a correlation of higher density levels of cytotoxic (CTL) and memory T lymphocytes (CD3+ CD45RO+) infiltrated in the primary tumor with increased survival rates of patients

According to recent findings, the GK-1 peptide can induce a M1 phenotype and promote the efficient activation of DCs, which could be leading to the maintenance of an effector response against tumor growth, capable of counteracting the immunosuppressive response due to T

Considering the possible mechanisms of action of GK-1 and the information available, we propose that this peptide can decrease tumor growth and metastasis by changing the tumor microenvironment. GK-1 appears to reactivate the immune system affected by the tumor-associated suppressive microenvironment, thereby allowing immune cells to become activated. Although more studies focusing on the anticancer effect of GK-1 are required, this research gives new evidence on the possible clinical uses of GK-1 beyond its well-established adjuvant effect.

These results have also provided us with the rationale to evaluate the effectiveness of the GK-1 immunotherapy to revert the exhaustion of peripheral T-cells in several types of cancer.

This work was supported by CONACyT (253891), Fundación Miguel Alemán, and the Programa de Investigación para el Desarrollo y la Optimización de Vacunas, Inmunomoduladores y Métodos Diagnósticos del Instituto de Investigaciones Biomédicas, UNAM.

The authors acknowledge the financial assistance of CONACyT to the doctoral students Jacquelynne Cervantes-Torres, Laura Montero-León, and Diana Torres-García from Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM), who received the fellowships 25243, 29951, and 245638, respectively. This manuscript is part of the doctoral thesis of the students from the Instituto de Investigaciones Biomédicas at the Universidad Nacional Autónoma de México.
