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Table 3. Gene silencing strategies for inhibition of TAM recruitment, survival, and reprogramming
siRNA
Therapy strategy Nanomaterial Function
target
Inhibition of TAM • CCR2 • Liposome It blocks the expression of the C-C chemokine receptor type 2 (CCR2) chemokine receptor,
recruitment siRNA which is essential for recruitment [104]
• VEGF • Inorganic In a lung cancer model, M2 peptide (M2pep)-functionalized Au nanoparticles loaded with
[105]
siRNA nanoparticle VEGF siRNA were designed for cancer immunotherapy by targeting TAMs
Inhibition of survival • CSF1R • Polymer An anti-CSF1R siRNA, with α-peptide (a scavenger receptor B type 1-binding peptide) linked
siRNA with M2 macrophage-binding peptide (M2pep) on the particle surface, is known to block
the survival signal of TAMs and deplete them from melanoma tumors [106]
Reprogramming • STAT • Liposome Protumor TAMs are generated by signal transducer and activator of transcription 3
siRNA (STAT3) signaling cascade, suggesting that inhibition of STAT3 can convert them to
antitumor M1 type macrophages [107]

has been shown to block immunosuppression by MDSCs in tumors and promote tumor-specific T cell
response [80]

MDSCs are heterogeneous and lack specific cell markers, which makes it challenging to study and utilize
them effectively . MDSCs have been shown to modulate therapeutic efficacy in immunotherapy, RT, or
[26]
chemotherapeutic approaches. Efficacy of adoptive T cell immunotherapy (ACT) is shown to be affected by
the presence of MDSCs in the TME, as MDSCs inhibit T cell proliferation and induce expression of
cytotoxic mediators, which are major requirements for the success of ACT [23,49] . MDSC depletion has also
[50]
been seen to improve the efficacy of RT . Chemotherapy by gemcitabine and 5-fluorouracil has been
shown to reduce MDSC numbers, which in turn reduces their immunosuppressive effects and helps enable
[81]
CD8+ T cell-dependent anticancer immune response . MDSC depletion and prevention of their trafficking
to the tumor site have been shown to improve antitumor immune responses, as shown by Highfill et al. in a
mouse model . IL-8 neutralization by HuMax-IL8 mAb in triple-negative breast cancer has been shown to
[82]
decrease the recruitment of PMN-MDSCs to the tumor site and facilitate tumor killing .
[83]
CANCER THERAPY USING MYELOID CELLS
Given the crucial role of immunosuppressive myeloid cells in tumor immune evasion, various therapeutic
strategies aimed at reprogramming myeloid cells from an immunosuppressive to immunostimulatory mode
have been explored. Table 4 highlights the therapeutic strategies of the myeloid cells cumulatively.

Myeloid cells in resistance to cancer therapy
Myeloid cells, especially TAMs, have been shown to play a pivotal role in tumor drug resistance. Drug
resistance in cancer has several causes, including genetic mutations and/or epigenetic modifications,
conserved but elevated drug efflux, and a variety of additional cellular and molecular pathways [84-87] .
Paclitaxel is an anti-microtubule drug from the taxane family that is used to treat ovary, breast, and non-
small cell lung cancers. The infiltration of macrophages in mammary tumors, as well as cathepsin levels,
increases after paclitaxel treatment. Macrophages conferred protection on cancer cells from paclitaxel
treatment in co-culture experiments by inducing cathepsins B and S expression, suggesting that combined
inhibition of TAMs with chemotherapy may be a strategy to overcome resistance . B-Raf is a
[88]
serine/threonine-protein kinase that functions in the MAPK/extracellular signal-regulated kinase (ERK)
signaling pathway and works downstream of RAS. In melanoma, the BRAF gene is frequently altered,
[89]
resulting in the B-Raf protein’s constitutive action . Concurrent therapy with the CSF-1R inhibitor
PLX3397 and the BRAF inhibitor vemurafenib resulted in increased antitumor responses in a murine model
of melanoma, owing to a considerable decrease in tumor-infiltrating myeloid cells and an increase in
tumor-infiltrating lymphocytes . In mice with pancreatic ductal adenocarcinoma (PDAC) tumors,
[90]