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Wong et al. Cancer Drug Resist 2023;6:768-87 https://dx.doi.org/10.20517/cdr.2023.58 Page 776

PI3K/AKT/mTOR pathway
Abnormalities in the PI3K/AKT/mTOR pathway are also another well-known mechanism of resistance in
[66]
breast cancer . The protein phosphatase and tensin homolog (PTEN) tumour suppressor is a negative
regulator of PI3K signalling and deletions in PTEN result in the enhancement of PI3K signalling [66,67] . PTEN
loss has also been associated with resistance to T cell-mediated immunotherapy by increasing the
[68]
expression of immunosuppressive cytokines, particularly VEGF . VEGF can contribute further to
immunosuppressive TME by recruiting suppressive immune cells such as myeloid-derived suppressor cells
[69]
(MDSC) and regulatory T cells (Tregs) .
Based on these preclinical findings, AKT inhibitors have been combined with ICIs to overcome this
resistance pathway. The phase Ib study evaluating the triplet combination of ipatasertib, atezolizumab, and
a taxane as first-line treatment for locally advanced/metastatic TNBC reported a promising ORR of 73%
irrespective of their PD-L1 status or PIK3CA/AKT1/PTEN alteration status . The BEGONIA study
[70]
(NCT03742102) is a phase Ib/II trial evaluating the combination of durvalumab with different novel
oncologic therapies designed for immune modulation, with or without paclitaxel as first-line treatment in
[71]
patients with metastatic TNBC. In arm 2 , the addition of capivasertib was studied, yielding an ORR of
53.3%. Importantly, there was a relatively high rate of G3/4 treatment-related adverse events of 73%,
although only 6.7% discontinued treatment due to adverse events.

Wnt/β-catenin pathway
The Wnt/β-catenin pathway is an important oncogenic signalling pathway involved in many essential
[72]
cellular processes . The activation of Wnt results in the accumulation of the transcriptional co-activator
β-catenin to initiate the transcription of several cell cycle genes and oncogenes such as Myc . The high
[73]
levels of β-catenin via the canonical pathway have also been shown in a murine study by Spranger et al. to
decrease the presence of CD103+ dendritic cell (DC) by reducing the expression of chemokine that attracts
[74]
CD103+ DC (CCL4), preventing the migration of DC into the TME . Consequently, this results in the
blocking of adaptive antitumour immunity . A study of TNBC by Castagnoli et al. showed that TNBC
[75]
stem cells are able to upregulate PD-L1 expression via the Wnt pathway .
[75]
JAK/STAT pathway
Interferon γ (IFN-γ) is a cytokine produced by activated T cells and antigen-presenting cells (APCs) that is
critical in immune cell activation via the Janus kinase 1 and 2 (JAK1/2) as well as signal transducers and
activators of transcription-1 (STAT1) pathway . Any mutation or epigenetic silencing of molecules in this
[76]
[77]
pathway allows tumours to escape its apoptotic or cytostatic effect . A study analysing melanoma patients
who were treated with ICI therapy and subsequently developed resistance noted that resistance was
[78]
associated with defects such as loss-of-function mutations in the JAK1/2 pathway . Another study of 16
melanoma patients observed that those who were non-responders to CTLA-4 inhibition harbor a much
[79]
higher rate of genomic changes in the IFN-γ pathway genes compared to those who responded .
Antigen presentation
A crucial feature of adaptive immunity is its ability to recognise antigens that are foreign or not “self”.
Cancer cells generally harbour accumulated somatic mutations and genomic instability within DNA coding
regions. Antigen peptide sequences that distinguish tumour cells are classified based on their unique cell
expression patterns . Tumour-specific antigens (TSA) refer to novel peptide sequences, i.e., neo-antigens,
[73]
that develop via mutations and are not present in normal healthy cells. Examples of mutations that result in
[80]
TSAs usually involve oncogenic driver mutations, such as mutations in the BRCA1/2 gene . The
presentation of these neoantigens by APCs via MHC-I molecules is critical in priming specific cytotoxic