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and chemotherapy backbone in the metastatic setting, just to name a few. Recent review articles have
discussed some of these topics [135,136] .

Further advancement in this field needs to be led by sound science with good preclinical evidence from
appropriate murine tumour models that can reflect the human immune environment. While this has
conventionally largely been restricted due to a limited selection of murine tumour models, novel syngeneic
tumour murine models have been better able to mirror the genomic heterogeneity of human cancer, and
recapitulate the TME so as to provide accurate results. It is hoped that the use of appropriate novel
syngeneic tumour murine models will allow us to further study ICI combinations effectively and
accurately .
[137]

Lastly, studies looking beyond immunotherapy-based treatments are also being investigated. One such area
is the study of the human gut microbiome, a host factor that influences not only the biology of tumour
development but also the modulation of its response and resistance to immunotherapy [138-140] . Consequently,
there are ongoing studies looking at modifying the gut microbiota in order to increase the efficacy of
immunotherapy treatment. These include interventions such as the use of antibiotics, probiotics, faecal
[141]
microbiota transplantation, and diet and prebiotics .

There is much to be anticipated in this evolving field of immunotherapy in breast cancer. While previously
thought to be an immunologically “cold” cancer with limited responses to ICI, this is certainly set to
change. The numerous ongoing trials evaluating ICIs in combination with novel therapies to overcome
resistance and exploit the immune system, as well as the development of innovative
immunomodulatory strategies, will allow us to further harness and expand the role of immunotherapy in
breast cancer.

DECLARATIONS
Authors’ contributions
Conceptualization: Wong RSJ, Ong RJM, Lim JSJ
Original draft writing: Wong RSJ, Ong RJM
Manuscript review and editing: Wong RSJ, Lim JSJ
All authors contributed to the article and approved the submitted version.

Availability of data and materials
Not applicable.

Financial support and sponsorship
JSJ Lim is supported by the NMRC (NMRC/MOH/00414). All other authors have no funding to declare.

Conflicts of interest
JSJ Lim has received honoraria from Astra Zeneca, Novartis, Roche, DKSH, MSD, Eisai, Pierre Fabre; has
advisory activity with Astra Zeneca, Novartis, Roche, DKSH, Pfizer and MSD; received research funding
from CTI biopharma, Daiichi Sankyo and Synthon pharmaceuticals; and has received travel grants from
Astra Zeneca and MSD.

Ethical approval and consent to participate
Not applicable.