Background
Breast cancer (BC) has the highest incidence rate worldwide and the highest mortality rate among cancers in women [
1,
2]. Treatments of BC mainly include surgery, radiotherapy, endocrine therapy, systemic chemotherapy, and antihuman epidermal growth factor receptor 2 (HER2)-targeted therapy. Individualized precision therapy is usually tailored to the clinicopathological and molecular characteristics of patients with BC. Despite significant advances in BC treatment, proximately 20% of BC patients may still relapse or metastasis relapse or metastasis, and treating them is still a challenge [
3].
Owing to the recent rapid developments, immunotherapy has gradually become an efficient treatment for cancers [
4], which targets the intrinsic immunity of the patients [
5]. The immunotherapeutic approaches include oncolytic viruses, immune checkpoint blockade (ICB) therapy, pattern recognition receptor-targeted therapies, adoptive cell transfer (ACT), and adjuvants [
6‐
8]. However, only a subset of patients with specific tumor types benefits from immunotherapy.
Because of the low infiltration of lymphocytes in breast tumors, BC was formerly deemed immunologically “cold” [
9]. However, increasing evidence has indicated the prominent heterogeneity of BC regarding the tumor microenvironment (TME) and immune infiltration [
10,
11]. Immunotherapeutic approaches in conjunction with classic treatments have been explored for maximizing anti-BC efficacy, especially in triple-negative breast cancer (TNBC). A large-scale clinical trial has shown that the combination of chemotherapy and pembrolizumab, a kind of programmed cell death 1 (PD-1) suppressants, could help in achieving significantly and clinically meaningful benefits in both disease-free survival and overall survival in programmed death ligand 1 (PD-L1)-positive ([combined positive score≥10) patients with advanced TNBC [
12,
13]. Nowadays, this combination therapy has become a recommended first-line treatment for advanced patients with PD-L1-positive TNBC. Furthermore, in patients with early TNBC, the addition of pembrolizumab to neoadjuvant chemotherapy, followed by adjuvant pembrolizumab after surgery, contributed to a significantly higher pathological complete response and longer event-free survival [
14]. Nevertheless, the research on the value and further application of immunotherapy in BC is far from enough.
The role of TME in diverse aspects of tumor development, such as vascularization, immunity, and tissue metabolism, has been demonstrated and is well-acknowledged [
15‐
17]. TME consists of carcinoma cells, extracellular matrix (ECM), stromal cells (e.g., vascular endothelial cells, myoepithelial cells, and fibroblasts), and immunocytes (e.g., B cells, T cells, natural killer [NK] cells, and macrophages). Immunotherapies facilitate the systemic immunologic monitoring and locally modulate the tumor immune microenvironment (TIME) [
18]. BC–TME has crucial clinical significance in patients with BC [
19]. For further research and application of immunotherapies in BC, it is imperative to reconstruct the BC–TME and investigate the cell interplays in BC–TME, which are environment-dependent intricate processes. Appropriate preclinical methods should be established that can reliably recapitulate the composition and functions of BC–TME. From cell co-cultures to different animal models, there are various models for immunotherapeutic research; however, they cannot completely recapitulate the intricate TIME of patients with BC at present. Nevertheless, the novel organoid models can simulate immunotherapy response and promote immunotherapy research. In this study, we summarize the common immune organoid models of BC and introduce their applications.
Conventional models for immunotherapy
Two-dimensional (2D) in vitro models are predominant preclinical models for various types of studies because they are cost-efficient, relatively simple, and adaptable to toxicity research and high-throughput screening [
20]. However, 2D models are not suitable for immunological research due to the following reasons: 2D models are often cellular monocultures and unable to recapitulate the entire fundamental cellular compositions and cell interplays in vivo, especially the interplays between ECM and immune cells [
21‐
23]; the carcinoma-derived cells may acquire substantial genetic alterations and are unable to represent TME and tumor heterogeneity of the native tumor tissue [
23,
24].
In vivo models are beneficial for the toxicology and efficacy research of classic drugs. But they cannot assess all types of immunotherapies, owing to the huge inherent disparities in immune systems between animals and humans [
25]. Patient-derived tumor xenograft (PDTX) models can partially recapitulate the cancer cell interplays with the stromal cells and ECM and partial interplays with the immune response [
23] and are already used for biomarker identification, preclinical drug testing, cancer research, and drug discovery [
8,
26]. Nonetheless, PDTX models still lack key immunity components of humans, such as circulating B and T cells. To solve this problem, humanized models of immuno-oncology are established by transplanting tumor fragments obtained from patients into the human immunocyte-bearing mouse model. However, the establishments of these models are fraught with challenges, considering the cost, yield, time, and complete immune compatibility [
6,
7].
Conclusion and perspectives
Immune organoids of BC can be successfully established under certain conditions. They can potentially serve as in vitro models to evaluate sensitivity and resistance to immunotherapy, analyze new therapeutic approaches, and determine personalized immunotherapy. But we still face some challenges, such as approaches to prolong the culture time of immune organoids, solutions to vascularization, and perfusion problems. In order to fully utilize these models as immunotherapy models for BC research, it is necessary to understand their advantages and disadvantages and address the challenges we face. We believe that organoids can become a great immuno-oncology tool in BC after their successful establishment. We look forward to relative clinical trials to explore their various application values in BC research, especially for precision medicine.
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