Cancers subvert the immune system in order to survive, but also to accelerate their growth. Macrophages are a part of the innate immune system, and have roles in wound healing. They become engaged by a tumor; tumor-associated macrophages assist in the rampant growth of tumor cells by supporting them in an analogous way to the support of regrowth in injured tissues. A cancer is, in many ways, the twisted reflection of regeneration. In place of the intricate dance between macrophages, stem cells, and somatic cells, there is instead an equally complex interaction between tumor-associated macrophages, cancer stem cells, and cancer cells. Better understanding of these interactions might lead to ways to sabotage a cancer by picking apart the signaling, or finding ways in which tumor-associated macrophages or cancer stem cells could be selectively targeted for destruction.
Cancer stem cells (CSCs) constitute a cancer cell subpopulation similar to the other stem cell types in terms of self-renewal and multilineage differentiation potential but drive tumor development besides heterogeneity and dissemination of cancer cells. Targeting CSCs for therapeutic purposes is a goal of the scientific community. Currently, cancer treatments target the bulk population of the tumor cells without identifying and targeting CSCs. The significant problem in this regard is the lack of identification marker/s specific for CSCs.
Macrophages are large specialized phagocytic cells that exist in tissues or at infection sites. They arise from monocytes in the bone marrow and perform different functions and roles in the microenvironments of normal and tumor tissue. Macrophages differentiate into classically activated subtypes: CD68 expressing M1 mainly involved in pro-inflammatory activities, and CD163 expressing M2, that promote anti-inflammatory processes. In tumors, tumor-associated macrophages (TAM) comprise up to 50% of the tumor mass, with M2 phenotype being most abundant in the TME. The primary signals provided by TAMs include interleukin 4 (IL-4) and transforming growth factor-beta (TGF-β). TAMs play a key role in tumor initiation, development, and cancer cell propagation.
TAMs promote tumor growth by inducing neoangiogenesis, supporting CSCs, and downregulating tumour-targeting immune cells' number and function. Due to the significance of the tasks in which TAMs are involved, TAMs are increasingly becoming principal targets of novel therapeutic approaches, especially in the field of nanomedicine. The roles, connections, and functions of the crosstalk between TAMs and CSCs have been studied in-depth during the recent past. The interactions may be direct or indirect, and the effects on CSCs include chemoresistance, preservation, and the capacity to differentiate. TAMs produce cytokines including milk fat globule epidermal growth factor 8 (MFG-E8); interleukin 6 (IL-6), which can activate STAT3; and the Hedgehog signaling pathway, which seems to be one of the causes of drug resistance. For example, in hepatocarcinoma, IL-6 promotes the expression of CD44, inducing tumor development.
In-depth understanding of interaction between TAMs and CSCs is needed to develop novel treatment strategies in future. In this direction, researchers have already reported the presence of CSCs in many solid tumors as the leading cause of cancer relapse and chemotherapeutic drug resistance. In addition to this subpopulation of cells, macrophages and other immune cells also participate in interactions that may aid or impede the fight against cancer. For this reason, the targeting TAMs offer a novel treatment option against cancer. We believe that targeting TAMs may trigger various stromal reactions in the tumor milieu that are difficult to predict, even if the variability from patient to patient is kept as a consideration. Targeting TAMs could not only inhibit the tumor microenvironment, but also renovate the tumor "soil" to build a tumor-suppressive microenvironment, thereby suppressing tumor development. This strategy may become an effective therapeutic intervention that may be used either alone or in combination with other therapeutic strategies to treat cancer.