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Tumor Discovery Immune and epigenetic therapies for TNBC

involved in anti-inflammation, tumor immune escape, cells in TNBC. The role of the TME in shaping TNBC
and immunoregulation. It promotes maternal tolerance disease progression and immune responses is very crucial,
toward the allogeneic fetus, suppresses transplant exhibiting both immunosuppressive and immunoreactive
rejection, regulates autoimmune disorders, and more. This properties. Subclassification of TNBC based on TIME
is achieved through Trp depletion and Kyn production. 119 subtypes aids in predicting outcomes and personalized

Over the past two decades, there has been significant treatments.
effort in drug discovery aimed at developing anticancer In TNBC, TILs are significantly elevated, impacting
small molecules that target both TDO and IDO1 enzymes patient prognosis and response to therapy, including
based on this hypothesis. Numerous IDO1 catalytic chemotherapy. Higher TIL levels correlate with better
inhibitors have been developed, each with unique therapy outcomes and a greater pCR rate in TNBC patients.
mechanisms of inhibition (competitive, noncompetitive, MDSCs play an important role in creating an
and heme-displacing compounds) and desirable qualities immunosuppressive TME, promoting tumor growth,
for therapeutic candidates, such as better selectivity, progression, and metastasis. Approaches targeting MDSCs
potency, oral bioavailability, and a favorable safety have shown promise in enhancing immune surveillance
profile. 120,121 Targeting IDO1 in cancer immunotherapy against tumors and restoring chemosensitivity. Tregs
has garnered considerable attention due to encouraging are found in high frequencies in TNBC tumors and are
preclinical research showing the antitumor effect of associated with unfavorable prognoses, although their
IDO1 blockade, either in combination with other ICIs or precise role remains complex- and context-dependent.
as monotherapy, in several animal models. The study
122
by Sono et al. explored the inhibitory mechanisms of Dysregulation of immune checkpoint molecules,
4-phenyl-imidazole (4-PI) on IDO1. The binding of 4-PI such as PD-1/PD-L1 and CTLA-4, through epigenetic
to IDO1’s heme iron was confirmed through a co-crystal mechanisms, contributes to immune evasion in TNBC. The
structure (PDB code: 2D0T). Subsequent optimizations role of epigenetic modifications, such as altered chromatin
led to the development of navoximod, a potent IDO1 architecture and DNA methylation, is significant in
inhibitor. When combined with atezolizumab, navoximod immune evasion and disease progression.
showed limited efficacy in clinical trials. Structural analyses DNMTis and HDACis have shown potential in
(PDB code: 6O3I) revealed that the imidazoisoindole ring reversing epigenetic modifications and enhancing anti-
of navoximod coordinates with heme iron and engages tumor immunity in TNBC. However, the interaction
in hydrophobic and hydrogen bonding interactions, between histone deacetylation and DNA methylation may
enhancing its inhibitory activity and stability. 123 lead to self-reinforcing silencing mechanisms, potentially
NO levels significantly influence the heme insertion compromising the effectiveness of monotherapy.
into IDO1. Studies have shown that NO can modulate Combining HDACis with DNMTis may offer synergistic
the availability and insertion of heme into IDO1, thereby benefits and improved outcomes in TNBC treatment.
regulating its activity. NO produced by inducible NO Nonetheless, challenges such as drug interactions, side
synthase can inhibit IDO1 activity by preventing heme effects, and patient adherence need to be addressed in
incorporation, which is crucial for IDO1’s catalytic combination therapies.
function. This regulation is particularly relevant in the
context of cancer, where the balance between NO levels 6. Recommendations and future directions
and IDO1 activity can affect the tumor’s ability to evade First, we recommend further exploration and refinement
immune detection and destruction. 124 of the subclassification of TNBC based on TIME subtypes.
By targeting this regulatory mechanism, there is This characterization can provide valuable insights into the
potential to develop therapeutic strategies aimed at heterogeneity of TNBC and its implications for treatment
reducing IDO1-mediated immunosuppression. This could response and patient outcomes. Utilizing advanced
enhance the efficacy of existing cancer treatments and technologies such as single-cell sequencing and spatial
improve anti-tumor immune responses, particularly in transcriptomics can enhance our understanding of the
TNBC, where IDO1 expression is often upregulated. diverse cellular compositions within the TME. Clinically,
integrating TIME subtyping into routine pathology
5. Key findings assessments can help predict treatment responses and guide
This review of the TNBC microenvironment and immune personalized therapeutic strategies for TNBC patients.
modulation highlights several key findings regarding Second, given the significant impact of TILs on TNBC
the relationship between the immune system and tumor prognosis and therapy outcomes, efforts should be made

Volume 3 Issue 3 (2024) 11 doi: 10.36922/td.3383