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Thomas et al. J Transl Genet Genom 2024;8:249-77 https://dx.doi.org/10.20517/jtgg.2024.15 Page 263

the immunosuppressive TME. Targeting TAMs, the predominant immunosuppressive cells in prostate
[264]
cancer, presents a promising therapeutic avenue for mCRPC treatment . Macrophages, once viewed as
phagocytic sentinels, now demonstrate diverse roles in maintaining tissue homeostasis. Tissue-resident
macrophages oversee the microenvironment, ensuring tissue integrity, facilitating cellular communication,
[265]
and regulating immunological balance . Conversely, monocyte-derived macrophages, recruited during
inflammation, adopt either the pro-inflammatory "M1" or anti-inflammatory/reparative "M2" phenotypes,
each characterized by distinct gene expression and metabolic pathways. "M1" macrophages rely on
glycolysis, producing inflammatory cytokines like IL-1β, IL-12, TNF-α, and reactive oxygen species, while
"M2" macrophages employ oxidative phosphorylation, secreting molecules such as arginase-1 and
[266-268]
TGF-β .
Despite the simplicity of the "M1/M2" dichotomy, current single-cell transcriptomic data suggest a more
[269]
complex landscape, acknowledging the high degree of macrophage plasticity and tissue-specificity . This
complexity has propelled macrophage reprogramming to the forefront as a promising therapeutic.
Macrophages' dynamic transition between "M1" and "M2" states in response to environmental cues has
become a focal point in disease treatment strategies, particularly by directing them toward an "M1"
phenotype to initiate inflammation and restore homeostasis.

In mCRPC, TAMs play dual roles: facilitate tumor progression, and induce immunosuppression within the
[270]
TME . Research also underscores TAMs' significant function in fostering resistance to anti-androgen
therapies. For instance, macrophages can induce ECM remodeling, reminiscent of wound healing processes.
Such macrophage-mediated ECM modifications correlate with anti-androgen resistance, particularly
through the activation of fibronectin-1 (FN1)-integrin alpha 5 (ITGA5)-tyrosine kinase Src signaling
cascade, induced by the cytokine Activin-A . Reprogramming these TAMs to an M1-like state may
[271]
disrupt these pro-tumorigenic activities. Transitioned M1 macrophages could potentially reverse the
immunosuppressive TME, attenuate ECM-mediated drug resistance, and amplify the efficacy of current
[272]
therapies .
Upregulated Src kinase activity in prostate cancer bone metastases, mediated by the Activin-A Receptor as
[273]
well, is associated with macrophage density and several ECM-receptor pathways . Targeting this activity
with the specific Src inhibitor eCF506 has shown promise in blocking enzalutamide resistance, emphasizing
its therapeutic potential in mCRPC management . Furthermore, strategies that modulate TAMs can
[271]
[274]
engender a more antitumoral phenotype . ICIs can induce M1 macrophage polarization, and the
depletion of Treg cells - protectors of the tumor-friendly milieu - by anti-CTLA-4 antibodies is contingent
[275]
upon macrophage-mediated actions . These insights affirm the premise that macrophage reprogramming
could play a crucial role in enhancing the impact of immunotherapies in mCRPC.

An alternate, emerging approach is through chimeric antigen receptor macrophages (CAR-M), which
leverages the natural tumor-homing ability of myeloid cells. This therapy has shown potential advantages in
infiltrating solid tumors and can release pro-inflammatory cytokines to improve the TME . Furthermore,
[276]
the combination of CAR-M with CAR-T cells has demonstrated synergistic action against cancer cells,
exceeding the effects of either therapy alone. This synergy suggests that CAR-M and CAR-T can
complement each other, enhancing tumor responses. Despite its promising antitumor activity demonstrated
in animal experiments, CAR-M therapy faces several challenges that need to be addressed. These include
optimizing the CAR structure by incorporating tandem activation domains or pro-inflammatory cytokines
to enhance its effectiveness and safety for clinical application .
[277]