**5. Small molecule inducers of Phagocytosis**

Small molecule activators of macrophages offer a potential alternative to traditional cancer treatments, such as chemotherapy and radiation therapy, and may also be used in combination with other cancer treatments for a more comprehensive approach to cancer therapy. The goal of using small molecule activators is to enhance the natural ability of macrophages to recognize and eliminate cancer cells, potentially leading to cancer elimination. This type of therapy is still in the early stages of development, but has shown promising results in preclinical studies and early clinical trials.

Some examples of small molecule activators of macrophages include:


#### **5.1 Cell-based therapies**

Phagocyte-based cell therapies are a type of cancer treatment that leverage the phagocytic properties of immune cells to eliminate cancer cells. One example of such a therapy is dendritic cell (DC) vaccines, which involve extracting dendritic cells from the patient's blood, enriching them with tumor-associated antigens, and then reintroducing them into the patient. The enriched DCs then travel to the lymph nodes, where they display the antigens to T-cells, eliciting an immune response against the cancer cells [75–77].

Additionally, researchers have developed enginnered macrophages and CAR (chimeric antigen receptor) macrophages as alternative forms of phagocyte-based cell therapy to combat cancer [78, 79].

#### **5.2 Dendritic cells based cancer vaccines**

Dendritic cells (DCs) are specialized antigen-presenting cells that originate from bone marrow progenitors. They can take up and process antigens through various mechanisms such as phagocytosis, receptor-mediated endocytosis, or micropinocytosis, depending on the type of antigen and their activation status. DCs can recognize antigens associated with pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). These processed antigens are presented on the surface of DCs by MHC I or MHC II molecules to CD4+ or CD8 + T-cells, respectively (**Figure 2**).

DCs can activate various immune cells including naïve and memory T-cells, natural killer (NK) cells, and natural killer T (NKT) cells, making DC vaccines a promising approach for cancer immunotherapy. Recent clinical trials have shown that tumor-antigen-preloaded DCs can initiate anti-tumor immune responses in patients, indicating the potential of DCs in cancer therapy.

The production of a DC vaccine involves several steps. First, tumor cells are obtained during surgical resection of the patient's tumor. These tumor cells contain specific antigens that are unique to that patient's tumor.

Next, the patient's peripheral blood monocytes are obtained through a process called leukapheresis. These monocytes are then differentiated ex vivo (outside the body) into dendritic cells, which are antigen-presenting cells that can activate the immune system's T-cells. The dendritic cells are then "trained" to recognize the patient's tumor cells. This is done by ex vivo pulsing the dendritic cells with tumor lysate or peptides derived from the patient's own tumor cells.

#### **Figure 2.**

*Illustration of dendritic cell maturation and antigen presentation to T cells. Figure downloaded from Biorender. com(on 02.15.2023).*

After the dendritic cells are trained, they are injected back into the patient. The injected DC-vaccine enables the dendritic cells to present the tumor antigens to the patient's CD4 and CD8 T-cells, which are part of the adaptive immune system. The T-cells then become activated a exerts highly specific immune response against the patient's tumor cells. This specific immune response can lead to the killing of the tumor cells, as well as the prevention of further tumor growth (**Figure 3**).

The aim of these vaccines is to activate the patient's immune system against the cancer cells, with the hope of inducing remission or eradication of the cancer.

#### **Figure 3.**

*Illustrates the mechanism of action of a DC vaccine in the body. The vaccine involves the ex vivo maturation and loading of dendritic cells with tumor-associated antigens (TAA). Once the vaccine is administered, the activated T cells that are specific to the TAA circulate throughout the body, searching for cancer cells that express the same antigen. Upon encountering a cancer cell, the T cells attach to it and unleash their cytotoxic activity. The figure was created using BioRender.com.*

Although still in the early stages of development, dendritic cell-based cancer vaccines have shown promising results in clinical trials, particularly when combined with other immunotherapy treatments (**Figure 3**) [80–82].

Follwing are some examples of dendritic cell-based cancer vaccines.

