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Wong et al. Cancer Drug Resist 2023;6:768-87 https://dx.doi.org/10.20517/cdr.2023.58 Page 774

surrounding microenvironment is thought to be a reflection of pre-existing antitumour immunity [49,50] , and
[50]
its presence is thought to be predictive of response to systemic anti-cancer treatment , as well as a
[24]
prognostic biomarker . TNBC and HER2-positive breast cancers have been observed to have a higher
number of TILs compared to hormone-positive breast cancers [51,52] . PD-L1 expression has also been
observed to be upregulated in HER2-positive breast cancer , and be predictive of response to ICIs in the
[53]
PANACEA and KATE2 studies [54,55] . Further in-depth discussion of ICIs in HER2-positive and hormone-
positive/HER2-negative breast cancers is beyond the scope of our current article, but has been extensively
reviewed [56-58] .

UNDERSTANDING AND OVERCOMING RESISTANCE MECHANISMS TO ICIS
Given that the earliest approval for ICI use in breast cancer came on 8 March 2019 for atezolizumab in
combination with nab-paclitaxel in metastatic TNBC based on the IMpassion 130 trial , the experience
[33]
and evidence available on resistance mechanisms specific to immunotherapy in breast cancer is scarce. In
addition, discounting tumour agnostic approvals, which form a very small proportion of breast cancer
patients as discussed above [36,37] , the approval for ICIs in breast cancer is now only limited to the TNBC
[59]
subtype, which constitutes only 15%-20% of all patients with breast cancer , and even so, only a subset of
them with high risk early-stage and metastatic disease. Hence, much of our understanding of resistance to
ICIs comes from the available data and research on ICI treatment as a whole from various other tumour
types.

Resistance pathways to ICIs can be tumour-intrinsic, e.g., alteration of certain genes or signalling pathways
within the tumour, or tumour-extrinsic, e.g., changes in components within the tumour microenvironment
(TME) other than the tumour cell itself . This can happen either from the outset, conferring primary
[60]
resistance whereby no response to treatment is noted, or after a period of observed response, highlighting
the concept of acquired resistance. As previously mentioned, breast cancers are known to be
immunogenically cold tumours, which contributes to their primary resistance to ICI. We will discuss the
various mechanisms of resistance by looking at both tumour-intrinsic and tumour-extrinsic pathways, and
how each of them might potentially be harnessed to overcome drug resistance [Figure 1].

TUMOUR INTRINSIC RESISTANCE MECHANISMS TO ICIS
Alteration of signalling pathways
There are several critical signalling pathways that control cell-cycle progression, apoptosis, and cell growth.
Alterations in any of these pathways can sometimes be exploited by cancer cells to escape immune
surveillance, leading to resistance to ICIs. Some of these pathways are known to be more commonly
mutated in breast cancer, for example, the mitogen-activated protein kinase (MAPK) pathway,
phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)
pathway, Wnt/β-catenin pathway and Janus kinase (JAK) and signal transducers and activators of
transcription (STAT) pathway . Hence, various combination therapies of ICIs with other therapeutic
[61]
agents to target each of these specific pathways are gaining traction and have shown promising preliminary
activity.

MAPK pathway
Signalling via the MAPK pathway induces the expression of various proteins such as vascular endothelial
growth factor (VEGF) as well as interleukin (IL)-8 that inhibit T cell recruitment and function . Inhibiting
[62]
the MAPK pathway can also upregulate major histocompatibility complex (MHC)-I, MHC-II, and PD-L1
expression, and enhance infiltration of TILs . Loi et al. had confirmed this observation in an analysis of
[63]
111 patients with TNBC who had been treated with neoadjuvant chemotherapy, and demonstrated that