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Advances in Radiotherapy
& Nuclear Medicine EZH2 inhibition in ARID1A-deficient TNBC

responses remain unclear, necessitating further research to immunotherapy resistance, including combinations of ICIs
elucidate the impact of tumor mutation burden or neoantigen with other anticancer agents, such as EZH2 inhibitors and
load, T-cell receptor repertoire, and expansion of specific T radiotherapy, as proposed in Figure 4. The dysregulation
cell clones on the immunologic and therapeutic responses to of epigenetic mechanisms, particularly through the
EZH2 inhibition and radiotherapy. In the context of TNBC, overexpression of EZH2, contributes to a suppressive TME
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PD-L1 expression was found to be increased in abscopal that hampers effective T-cell responses. This is important in
tumors following spatially fractionated radiotherapy (SFRT) TNBC, where overexpression of EZH2 has been associated
in a murine TNBC model (4T1). The intratumoral immune with increased PD-L1, but low TILs. By targeting EZH2,
cell composition in these abscopal tumors exhibited the TME could potentially be remodeled to enhance
significant increases in activated CD4 and CD8 T cells. the infiltration and activity of TILs that are crucial for
+
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SFRT, a novel radiation technique that applies ablative mediating anti-tumor immunity. In this context, BAF250a
doses to tumor subvolumes while sparing surrounding immunohistochemistry could serve as a useful biomarker.
tissues, results in highly heterogeneous dose deposition Patients with low BAF250a protein expression as a result
that may enhance the immune-rich infiltrate within the of low ARID1A gene expression may benefit from EZH2
targeted tumor, promoting improved antigen presentation inhibition. This inhibition could upregulate PIK3IP1
and activated T cells in non-irradiated tumors. Different expression, suppress tumor cell growth, and potentially
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radiation regimens elicit distinct immune responses, and restore previously repressed MHC-I expression, thereby
1,6
since SFRT consists of a heterogeneous dose distribution improving the efficacy of immunotherapy. Given that
often delivered in a single fraction, its immune effects may ARID1A mutations impair DNA repair pathways, this could
differ from standard fractionation. In a murine model of lead to increased sensitivity to therapies that induce DNA
pediatric glioblastoma, although both tazemetostat and damage, such as radiation. The addition of radiotherapy
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standard fractionation radiotherapy given as monotherapies may amplify the effects of immunotherapy through the
improved animal survival, the combination of tazemetostat release of tumor antigens, upregulation of PD-L1, and
with radiation did not further improve survival compared an increase in immune-rich infiltrate within the targeted
to either treatment alone, indicating a lack of additive volume of tumor, as well as potentially decreasing EZH2
or synergistic effects. Although the mechanism of protein expression. Despite the effectiveness of EZH2
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resistance was not further evaluated in the glioblastoma inhibitors in reducing H3K27me3 repressive marks to
model, analysis of atypical teratoid/rhabdoid tumors and improve response in other cancer types, they have not
medulloblastoma remnant/recurrent tumors treated with been observed to sufficiently inhibit the proliferation of
cisplatin in combination therapies revealed reduced levels most breast cancer cells as a monotherapy, possibly due
of EZH2 protein expression, H3K27me2, and H3K27me3, to the lack of effects on total EZH2 protein levels. This
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alongside a marked increase in the tumor cells exhibiting finding suggests that the protein expression of EZH2
absence of or low EZH2 expression. This finding suggests itself, rather than its methyltransferase activity, may be
that inter-tumoral heterogeneity may have contributed to more crucial in the development and progression of
tumor recurrence. The immunocompromised animal breast cancer, including TNBC, highlighting the potential
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model used in this study may not have adequately evaluated use of EZH2 selective degraders, such as MS1943, or
the immunomodulatory effects of radiation; thus, the agents that inhibit both the methyltransferase activity
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combination therapies may have been insufficient to deplete and degrade EZH2, such as IHMT-337. Although EZH2
the cells with no or low EZH2 expression. This limitation inhibitors are not as effective as a monotherapy in TNBC,
highlights the importance of evaluating immune effects and given that residual H3K27me3 has been shown to persist
tumor heterogeneity in models of combination therapy, in TNBC cells after knockout of endogenous EZH2, there
including single-cell sequencing and spatial single-cell is still merit in exploring combinations of EZH2 inhibitors,
analysis, to help understand drug resistance at the single- such as tazemetostat, with ICIs. 44
cell level. 113 Precision oncology utilizes the molecular profile of
6. Conclusion tumors to tailor more precise and personalized therapies
for distinct patient groups who differ in both susceptibility
TNBC is a heterogeneous disease characterized by to disease and responses to treatments. Epigenetics,
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transcriptional diversity and varying immune cell which influences gene expression and cellular phenotypes
compositions across its subtypes. ICIs have shown limited beyond the DNA sequence, plays an important role in this
efficacy in TNBC, marked by a high incidence of primary approach. As such, epigenetic modifications are prime
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resistance and the development of adaptive resistance. targets for therapeutic intervention. When combined
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Therefore, strategies are needed to overcome this strategically with immunotherapy in TNBC, this approach

Volume 3 Issue 1 (2025) 39 doi: 10.36922/arnm.5132