New Approaches in Gastric Cancer Immunotherapy

Abstract

Cancer has an inferior prognosis in most cases and is often challenging to treat. Gastric cancer (GC), which is among leading causes of the top five malignant tumor deaths worldwide and whose incidence is increasing every day, is no exception. GC is frequently diagnosed at a progressive or metastatic stage of the disease. At this stage, the clinical effectiveness of conventional treatments such as surgery and chemotherapy is limited, and the median overall survival is reduced to only about a few months. The tumor microenvironment (TME) and the specific conditions that govern it, concurrently with multiple mutations, have significantly increased the resistance of cancer cells. However, the study of molecular biology, cell signaling pathways, and immune system function provides a new approach using immunotherapy such as immune inhibitors, T cell transfer therapy, monoclonal antibodies (mAbs), therapeutic vaccines, etc. to overcome cancer resistance. In addition, the use of nanoparticles (NPs), especially theranostic NPs permits for better monitoring of the response during treatment, and its combination with immunotherapy, promising strategies for providing a new treatment. This chapter provides an overview of these new advances in treating GC cancer.

1. Introduction

Gastric cancer (GC) is the fifth most prevalent cancer and the third leading cause of cancer-related death. The highest incidence of GC occurs in East Asia, followed by Eastern and Central Europe, and it is more prevalent in men. Because of the poor prognosis, many GC cases are diagnosed at advanced stages, limiting treatment options, and increasing mortality [1, 2]. Exposure to Hp, dietary risk factors, obesity, tobacco, meat, alcohol consumption, genetics, and socioeconomic status play a role in its development. More than 95% of GCs are adenocarcinomas classified by anatomic location and histologic type (Table 1) [3, 4, 5, 6, 7, 8, 9]. GC is generally treated with a combination of surgery, endoscopy, and chemotherapy, which can have side effects that can have a substantial influence on patients’ quality of life. The physical removal of malignant tissue is a key component of stomach cancer therapy. Minimally invasive procedures like laparoscopic surgery and endoscopy are used for early detection and removal of tumors. Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are two endoscopic methods routinely used to remove early-stage stomach tumors. Despite its serious side effects, chemotherapy is still used as a treatment for advanced stomach cancer. Combination chemotherapy treatments have been found to enhance survival rates. Nausea, vomiting, exhaustion, and hair loss are some of the side effects of chemotherapy, which can be severe. On the other hand, the tumor microenvironment (TME) and multi-drug resistance by mutations in cancer cells and ABC family pumps (ATP-binding cassette) reduce its therapeutic effect. New treatment methods like immunotherapy and nanoparticles are being used to target and eliminate cancer cells. In the following sections, we will discuss all the above in detail [10, 11, 12, 13, 14].

Gastric cancer
Anatomic location		Histological type (Lauren classification)
Cardia (Proximal)	Non-cardia (Distal)	Diffuse	Intestinal
Mainly in developed countries (more common in Western countries) Risk factors: smoking (also in combination with drinking), consumption of food containing carcinogens, and exposure to Epstein-Barr virus (EBV) less lymph-node metastasis, good differentiation, Bigger in size, poor differentiation Molecular pathology: CIN and EBV type Survival: Higher 5-year survival rate	Mainly in developing countries (more common in East Asian populations) Risk factors: H. pylori infection (strong correlation), smoking, high-salt diet, food with carcinogens more lymph-node metastasis, Bigger in size, poor differentiation Molecular pathology: MSI type Survival: Lower 5-year survival rate	Is correlated with non-cardia prevalent in low-risk areas mainly associated with heritable genetic abnormalities frequently occurs in the gastric antrum diffusely infiltrating the gastric wall in a desmoplastic stroma characterized by poorly differentiated and discohesive tumor cells that may have either a signet-ring or non-signet-ring morphology. tumor cells lack adhesion	Is correlated with cardio more frequently in high-risk areas mainly found in the cardia and gastric fundus most commonly occurs in elderly male is more associated with environmental factors tumor cells exhibit adhesion are arranged in tubular or glandular formations affects the gastric antrum

Table 1.

The categorization and features of adenocarcinoma in GC.

2. Tumor microenvironment

The extracellular matrix that encompasses a range of cells, including cancer cells, cancer-associated fibroblasts (CAFs), pericytes, and other immune cells, is known as the TEM. The milieu around tumors, primarily made up of stromal and immunological cells, continuously affects the tumor cells [15].

2.1 Cancer-associated fibroblasts (CAFs)

About 70% of the cells in tumor tissues are CAFs, which are significant elements of malignancies such as GC [16]. They control processes such as angiogenesis, chemoresistance, and metabolic reprogramming, making them crucial in determining the spread of cancer. CAFs particularly control GC cell signaling, encouraging migration, invasion, and proliferation. They can also control immune cell activity and induce hypoxic or angiogenic circumstances through various signaling pathways. Furthermore, by secreting cytokines and chemokines, expressing cell surface receptor proteins, and remodeling the extracellular matrix (ECM), CAFs can control immune cell activity and their location and movement within the TME [17, 18, 19, 20, 21]. Subtypes of CAFs that co-expressed FAP and INHBA markers were discovered to be connected with a more advanced stage in the TME of GC. Myofibroblasts, pericytes, eCAFs, and iCAFs are the four main subpopulations of fibroblasts that were found to contribute to diffuse GC carcinogenesis. iCAFs contribute to diffuse GC carcinogenesis and may be implicated in DGC’s de novo carcinogenesis. CAFs not only shape the ECM but also supply signaling molecules that change the behavior of tumors and promote tumor survival. The Wnt/PCP signaling pathway is critical for invasion and metastasis in GC. CAFs generate WNT5A, which is the essential PCP ligand, and GC cells respond to this signal by enhancing polarized migration. CAFs secrete certain biological molecules such as Transforming Growth Factor-β (TGF-β), IL-6, and Epidermal growth factor (EGF) to promote tumor malignant phenotype, which includes tumor neovascularization and immune evasion, ultimately resulting in tumor deterioration. CAFs can also control tumor metabolism by creating an acidic milieu that inhibits the function of immune cells. Furthermore, tumor cells can exploit the metabolites of pyruvate and lactic acid generated by CAFs as nutrients to promote their proliferation [22, 23, 24, 25, 26, 27].

2.2 Immune cells

For immune editing and immunosurveillance against cancer, the host immunological response is essential. Target cells for immunotherapy include natural killer (NK) cells, dendritic cells (DCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), T cells, B cells, and regulatory T cells (Tregs). These cells are found in the TEM [28, 29, 30]. Through a variety of tumor cells can avoid immune system recognition and elimination. M2 TAMs, N2 TANs, MDSCs, regulatory B cells (Bregs), effector Tregs (eTregs), and inhibitory targets on different immune cells are among them that are important in tumor immune escape while tumor-infiltrating DCs, NK, M1 TAMs, and N1 TANs are helpful in anti-tumor immunity (Figure 1) [30].

Figure 1.

Immune cell-targeted treatment can be accomplished by either boosting anti-tumor immune cell counts or functions or by decreasing immunosuppressive cell counts or functions [30]. Copyright 2022 Frontiersin.

2.2.1 Dendritic cells (DCs)

Dendritic cells play a crucial role in activating T cells and bridging innate and adaptive immunity. Maintaining a sufficient density of mature DCs within tumors is essential for prolonged life of patients with advanced GC. There are two types of DCs: conventional DCs (cDCs; sometimes called myeloid DCs) and plasmacytoid DCs (pDCs) pDCs have gained interest in recent years for their ability to present antigens, secrete cytokines, and promote the proliferation and functionality of immune cells [31, 32].

2.2.2 Natural killer cells

NK cells play a crucial role in regulating the immune system against cancer cells and intracellular viruses. They identify tumor cells via NKG2D and eliminate them using perforin, death receptor signaling, or granzymes that generate cytokines and chemokines [33, 34, 35]. NK cells contain inhibitory receptors on their surface, which allows tumor cells to connect to them and evade NK cell killing. On the other hand, excess TGF-β, together with other chemokines and anti-inflammatory cytokines, can prevent NK cell activation in the TEM; produce some immunosuppressive factors, and downregulate NK cell activating receptors such as NKp30, NKp44, NKG2D, and CD16 as well as co-receptors including NKp80 and DNAM-1. It also upregulates checkpoint receptors such as TIGIT, TIM-3, LAG-3, and PD-1 [36, 37, 38].

2.2.3 Tumor-associated macrophages

Macrophages are a type of immune cell that infiltrate solid tumors. They are divided into two subgroups: M1 and M2. M1 macrophages have proinflammatory effects and produce High amounts of TNF-α, IFN-γ, IL-1β, IL-6, IL-12, CXCL9, and CXCL10 that stimulate type 1 (polarizing and recruiting Th1) responses aiding in the elimination of infections and tumor cells. On the other hand, M2 macrophages have anti-inflammatory effects and produce TGF-β1 (TGF-β1), IL-4, and IL-10 that have tumorigenic qualities [39, 40, 41, 42]. Macrophages play a crucial role in gastric inflammation during H. pylori infection. In GC tissue, macrophages are more abundant and their gene expression patterns are diverse. Macrophage-GC cell crosstalk contributes to the development of an immunosuppressive milieu and the progression of GC. M2 features are linked to a poor prognosis in many tumor types [43, 44, 45, 46, 47].

2.2.4 Tumor-associated neutrophils

As the initial line of defense against infection and inflammation, neutrophils play a crucial role in Innate immune responses. Neutrophils are associated with a worse prognosis in GC patients and are abundant in GC tissue [48, 49, 50]. Neutrophils are one kind of immune cell that promotes angiogenesis and inhibits the anti-tumor immune response, which contributes to the development of tumors [32]. GC-derived GM-CSF suppresses T-cell activity to advance GC by activating neutrophils and eliciting PD-L1 expression via the JK-STAT3 signaling pathway. Additionally, TANs secrete cytokines that aid in GC invasion and migration, including IL-1β, IL-6, IL-8, IL-17a, and IL-23 [48, 51, 52].

2.2.5 Myeloid-derived suppressor cells

The primary role of myeloid-derived cells, or MDSCs, is immunosuppression. They are a very diverse collection of cells. Malignant tumors with MDSC growth had a poor prognosis and were linked to treatment resistance. Increased MDSC levels were linked to later tumor stages, a worse prognosis, increased mortality, and a higher chance of tumor progression and recurrence in GC patient’s survival [53, 54, 55]. These relationships were also seen between MDSC levels and the cancer stage. MDSCs are involved in the production of immunosuppressive TME as well as the advancement and metastasis of tumors (Figure 2) [57, 58, 59].

Figure 2.

The processes via which gastrointestinal (GI) cancer is immunosuppressed by MDSC. MDSCs block the activity of DCs, prevent DCs from presenting antigens to CD4⁺ T cells, repress the growth and function of NK and T cells, decrease CD8⁺ T-cell infiltration, support M2 macrophage development, and stimulate the expansion and immunosuppression of Tregs. Moreover, nitric oxide (NO) generation and TGF-β-induced suppression of NKG2D have an impact on ADCC function and NK cell anergy, respectively. To encourage the proliferation and metastasis of GI cancer cells, MDSCs produce exosomes, matrix metalloproteinases (MMPs), and VEGF [56]. Copyright 2021 Wiley.

2.2.6 B cells

In addition to acting as APCs, B cells also create and ingest cytokines including IL-6, IFN-γ, and TNF-a, which help to develop CD4⁺ and memory T cells [60]. Research has demonstrated that effector T cells, NK cells, and TAMs, as well as T cells and other immune cells, are the primary mediators of antitumoral activity, which is inhibited by a subset of B regulatory cells called Bregs [61].

2.2.7 T cells

T lymphocytes come in different varieties: helper T cells (CD4⁺ cells), Tregs, and cytotoxic T cells (CD8⁺ cells). The TME’s CD8⁺ T cell subset is widely regarded as having immunological activation to produce antitumor effects, and the prognosis and treatment results of GC malignancies are strongly correlated with the subsets’ variety and density. Tumor prognoses vary depending on different T cell subsets. T-cell subsets that are advantageous to the prognosis and survival of GC include those with a high T helper (TH)1/TH2 ratio, high CD45RO memory T cells, and high levels of infiltration of CD8⁺ and CD4⁺ T cells [62, 63, 64].

2.2.8 Regulatory T cells

From 5–10% of peripheral CD4⁺ T cells are Tregs, which are responsible for maintaining immunological tolerance linked to tumor immunity. Numerous investigations have documented the significance of Tregs as a constituent of immune-suppressive cells, which expedite the growth of tumors in diverse malignancies by inhibiting T cell proliferation, antigen presentation, and cytokine generation. Based on how FOXP3 and CD45RA are expressed, TME Tregs may be divided into three groups: effector Tregs (eTregs) (FOXP3highCD45RA⁻), naïve Tregs (FOXP3lowCD45RA⁺), and non-Tregs (FOXP3lowCD45RA⁻). Non-Tregs can release pro-inflammatory cytokines but are unable to have an inhibitory impact. The function of eTregs is persistent and has substantial suppressive activity, while naïve Tregs only exhibit mild suppression [65, 66, 67]. In Figure 3, the various T cells, B cells, and Tregs are discussed concerning the GC microenvironment; Figure 4 also illustrates the significance of TAMs, NK cells, DC cells, and neutrophils in this context.

Figure 3.

The functions of various B cells, Tregs, and T cells in the stomach cancer microenvironment. In GC, certain Tregs and dysfunctional CTLs accelerate disease progression, while specific T cell subsets indicate poor outcomes. Conversely, CXCR5+ CD8+ T cells and CD103+ Trm cells are associated with better survival. PMN-MDSCs contribute to immunosuppression as cancer develops. Elevated CD73 expression in tumors enhances CD8+ T cell infiltration. Reduced expression of homing receptors in Aim2−/− mice leads to increased gastric CD8+ T cell frequency and metaplasia. Higher levels of NKG2D correlate with improved survival, as it interacts with tumor cells’ MICA/B and ULBPs. CD155 on tumor cells inhibits TIGIT+ CD8 T cells’ glucose uptake, diminishing their function. ICOS+ CD4+ T cells hinder CD8+ T cell proliferation, hastening disease advancement [29]. Copyright 2023 Springer.

Figure 4.

The functions of DC cells, neutrophils, NK cells, and TAMs in the GC microenvironment. In gastric cancer microenvironment, TAMs release immunosuppressive chemicals like CH13HL1, CXCL8, and CCL5, promoting tumor growth. Neutrophils’ secretion of MMP-9 and IL-17 correlates with poor prognosis. IL-33-driven mast cell buildup, facilitated by macrophage mobilization, contributes to GC progression in certain animal models. High levels of CD68+, CD163+, and IL10+ macrophages correlate with decreased survival rates. DC-SIGN+ macrophages elevate FOXP3 Treg levels, associated with lower overall survival. TAMs reduce NK cell percentage and function, while NK cells express CD16 and exhibit direct antitumor effects. Poor prognosis in GC patients is linked to high CD11b levels in DC cells, which lowers MHC class II expression. Neutrophils, driven by GC cell-derived exosomes and GM-CSF, promote tumor migration and enhance their own survival [29]. Copyright 2023 Springer.

We have summarized the findings of various studies to enhance understanding regarding the role of immune cells, such as T cells, TAM cells, B cells, NK cells, DC cells, neutrophils, and cytokines secreted by stromal cells in GC progression. You can find this summary in Table 2 for your better understanding.

Immune cells	Cancer type	Functions	Ref.
Dendritic cells
DC cells	GC	foreseen prognosis is unsatisfactory	[68]
Plasmacytoid DC cells	GC	Improved the efficiency of can-; cer treatments	[31]
Natural killer cells
NK cells	GC	Foresaw a more satisfactory 5-year survival rate compared to lysis activity of less than 25%	[69]
NK cells	GC	Effectively, trastuzumab-targeted tumor cells with a potent killing	[70]
NK cells	GC	Compared to low NK cell density has a more favorable prognosis GC	[71]
NK cells	GC	Survival is predicted to be longer	[72]
NK cells	GC	Tumor cells exhibit limited immune evasion.	[73]
NK cells	GC	Predicted better OS	[74]
High-affinity NK cells	GC	Induced direct antitumor effects	[75]
Tumor-associated macrophages
TAMs	GC	Prompted HMGB1 expression contributes to chemoresistance to 5-Fu	[76]
TAMs	GC	Boosted PD-L1 expression and; tumor metastasis	[77]
TAMs	GC	Impaired NK cell proportion; and function	[78]
TAMs	GC	Enhanced DNMT1 and low GSN expression to promote tumor growth	[79]
DC-SIGN+ TAMs	GC	Indicated poor OS and resistance to ACT such as 5-Fu	[80]
CD68+ CD163+ not MARCO+ TAMs	Gastroesophageal adenocarcinoma	Indicted poor survival	[81]
IL10+ TAMs	GC	Promoted regulatory T cell infiltration and CD8+ T cell dysfunction	[82]
Neutrophils
Neutrophils	GC	Induced tumor migration	[83]
Neutrophils	GC	Executed Immunosuppression	[49]
Neutrophils in the peripheral; blood	GC	Indicated poor prognosis	[84]
Myeloid-derived Suppressor cells
PMN-MDSCs	GC	Executed immunosuppressive; function	[85]
T cells
CD8+ T cells	Gastric and gastroesophageal junction (G/GEJ) adenocarcinomas	Shortened PFS and OS	[86]
CD8+ T cells	GC with high CD73 expression	The phenotype of the CD8^+ T cells indicated that they were dysfunctional.	[87]
CXCR5 + CD8+ T cells	GC with TNM II + III; stage	Benefited from ACT	[88]
CXCL13+ CD8+ T cells	GC	Indicated poor prognosis	[89]
(ICOS+) CD4+ T cells	GC	Impeded the proliferation of CD8+ T cells	[90]
Foxp3+ RORγt+ T cells	GC	Predicted poor overall survival	[91]
Tumor-infiltrating γδT cells	GC with TNM II + III; stage	Benefited from 5-Fu ACT	[92]
CD69+ CD103+ Trm	Gastric adenocarcinoma	Predicted better survival	[93]
HLA-1-preserved type/PDL1+	Microsatellite-unstable GC; tumors	Indicated good prognosis	[94]
TIM3+ cells	GC	Had poorer OS and disease-free; survival (DFS)	[95]
Regulatory T Cells
TNFR2+ Tregs	GC	Promoted the GC progression	[96]
CD4 + CD25 + FOXP3+ Tregs	GC	Helped immune-suppressive roles of Tregs	[97]
CD45RA − CCR7− Tregs	GC	Exerted immunosuppression	[98]
CD4+ FOXP3+ CD25high Tregs	GC	Exerted Immunosuppression	[99]
FOXP3+ Tregs	Stage I–II GC patients	Foreseen more acceptable prognosis	[100]
B cells
B regulatory cells	GC	Inhibited antitumoral activity	[61]
CD20+ B cells	GC	Prospered disease-free survival and overall survival rate	[101]
Cytokines or chemokines	Cancer type	Functions	Ref
CCL28	GC	Drove GC tumor progression	[102]
IL-9	GC	Achieved additional benefits from 5-Fu-based adjuvant chemotherapy and Lengthy OS	[103]
IL-15	GC	Promoted tumor progression	[104]
IL-17	GC	Benefited from adjuvant chemo-; therapy	[105]
IL17B	GC	Accelerated cancer stem cell tumorigenesis and self-renewal	[106]

Table 2.

A review of the immune system’s role in GC disease progression, by different immune cells, cytokines, and chemokines.

3. Resistance to the treatment of gastric cancer

GC is known for its resistance to standard treatments like chemotherapy and radiotherapy. Immunotherapy is a promising approach, but its effectiveness is often hindered by TEM of GC. Surgical resection with lymphadenectomy is the primary treatment strategy for GC. Surgery is the primary option for GC due to its resistance to chemotherapy and radiation [107, 108]. The TEM in GC is distinct from normal tissue, leading to fluctuations in glucose, lactate, oxygen tension, and acidic pH. Glycolysis leads to lactic acid production and subsequent tumor acidosis. Aggressive tumors rely heavily on glycolysis for energy production, even in the presence of adequate oxygen, exacerbating the acidic environment [109, 110].

3.1 Hypoxia

GC microenvironment is characterized notably by hypoxia and inflammation. Hypoxia, defined as a reduction in normal tissue oxygen levels, emerges due to rapid tumor cell proliferation surpassing the oxygen delivery capabilities of existing blood vessels. This condition triggers a series of cellular responses in tumor cells, enabling them to adapt and thrive in this low-oxygen environment. These cells undergo a range of molecular and physiological adaptations under hypoxic conditions, which often include upregulation of hypoxia-inducible factors (HIFs), alterations in metabolic pathways such as a shift towards anaerobic glycolysis, and the activation of survival and proliferative signaling pathways [111, 112, 113]. hypoxia in TEM is linked to poor clinical outcomes and treatment resistance in GC. Hypoxia triggers hypoxia-inducible factor-1 (HIF-1), which regulates the expression of many cancer-promoting molecules. HIF-1 is crucial in promoting angiogenesis, which is vital for tumor growth and spread in hypoxic conditions. Hypoxia also triggers the production of immune checkpoint molecules like PD-L1, which naturally slow down T-cell activity. Overexpression of PD-L1 hinders the effectiveness of immunotherapies, like checkpoint inhibitors, that aim to activate the immune system against cancer cells. Hypoxic GC cells show higher levels of PD-L1 expression, which contributes to the evasion of immune surveillance [30, 114, 115, 116].

3.2 Oxidative stress

Oxidative stress affects the resistance of GC to immunotherapy. In an oxidative stress state is a lack of balance between the body’s antioxidant defenses and the production of reactive oxygen species (ROS). High levels of ROS in GC can lead to genetic mutations, cancer cell proliferation, and metastasis, which often result in an increased resistance to cancer therapy, including immunotherapy [117, 118, 119]. For instance, oxidative stress can impair the effectiveness of T cells, a crucial part of the immune response in immunotherapy. However, targeting oxidative stress in treating GC is challenging due to the complex role of ROS in cancer biology, where it can both promote and inhibit tumor growth. It also requires sophisticated techniques and a deep understanding of tumor physiology to accurately assess and modulate oxidative stress levels within tumors [120, 121].

3.3 Acidosis

Changes in metabolic processes, specifically the Warburg effect, cause acidosis in tumors. The cancer cells consume glucose through glycolysis instead of oxidative phosphorylation, which results in the production of lactic acid. This, in turn, lowers the pH of the environment surrounding the tumor [122, 123]. This can impair the effectiveness of immunotherapies by inhibiting the function and survival of T cells and upregulating immune checkpoint molecules. The acidic environment also inhibits the effector functions of activated CD8+ T-cells. The study of Wu shows that acidic paracortical zones in lymph nodes inhibit the effector functions of activated CD8+ T-cells and hinder T-cell glycolysis. This low pH, is a result of the acid inhibition of monocarboxylate transporters (MCTs), leading to a decrease in the glycolytic rate [124]. Despite this, the acidic environment does not prevent the initial activation of native T-cells by DCs. Low pH conditions reduce cytokine production and proliferative capacity of T cells, which are crucial for their cancer-fighting abilities [125, 126]. Acidosis can also upregulate PD-L1 expression, contributing to the resistance to immunotherapy [127, 128].

4. New approaches in cancer immunotherapy

Despite advancements in GC treatment, there’s debate on the most effective approach. Multimodal treatments have improved patient survival, but over 70% of patients cannot be rescued. The side effects of therapy can lower the quality of life, which can impact the outcome. This fact has made researchers explore alternative approaches to managing GC [129, 130]. For GC treatment, there are several therapeutic methods with a different level of invasiveness from surgery to adjuvant therapies yet surgery is considered the priority therapy. Although, whether preoperative or postoperative, has shown improvement in the overall outcome of GC treatment, each of the conventional therapies comes with a spectrum of complications, ranging from severe to mild. Despite the radiotherapy, chemotherapy, and chemoradiotherapy have advanced, surgical resection remains the primary treatment option for GC. However, it is a high-risk procedure with significant morbidity and mortality, especially in elderly patients, has a lower tolerance for anesthesia and surgery due to a decline in organ function and an increase in internal diseases. While postoperative mortality has decreased by more than 50% in four decades, significant surgical morbidity following gastrectomy continues to pose challenges [131, 132]. Chemotherapy has been found to have comparable or better survival rates compared to surgeries for GC. Palliative chemotherapy enhances survival rates without impacting the quality of life significantly. Nausea, vomiting, and diarrhea are some common side effects However, acute chemotherapy complications like GI hemorrhage, perforation, nausea, vomiting, diarrhea, and typhlitis, from neutropenia by chemotherapy manifest as localized inflammation in the caecal wall [133, 134, 135]. Other approaches, such as radiation therapy, have been investigated to improve outcomes. However, radiation therapy can have severe side effects such as skin problems, diarrhea, fatigue, and low blood cell counts. Patients may encounter GI side effects [136, 137].

4.1 Novel immunotherapy methods

Immunotherapy emerged as a potent clinical approach to cancer therapy. The quantity of approved immunotherapy drugs has been steadily rising and there are also numerous treatments undergoing preclinical development and clinical trials. Immunotherapies for GI cancers include a range of approaches such as checkpoint inhibitors, cancer vaccines, adaptive cell transfer, and cytokines [138, 139, 140]. There are also complications with conventional immunotherapy methods such as Colitis secondary to immunotherapy coupled with diarrhea, abdominal pain, nausea, and vomiting. However, research has led to advancements in immunotherapy and other novel approaches to address these limitations. Subsequently, novel approaches to GC treatment are also being discussed [141, 142, 143, 144].

4.1.1 Immune checkpoint inhibitors (ICIs)

T cells combat cancer by recognizing antigenic peptides presented on the Human Leukocyte Antigen (HLA) through T-cell receptor (TCR). This process is called immune surveillance and prevents tumor development. TSA is a specific target antigen for TCR on tumor cells. When the immune system becomes “blind” to TSA, tumors can grow uncontrollably, a phenomenon known as “tumor escape”. Immune checkpoints serve as intrinsic components of the immune system, responsible for moderating the strength of immune responses to prevent harm to healthy cells. They come into play when proteins on T cells’ surface, recognize and interact with partner proteins on other cells, including certain tumor cells. These partner proteins, known as immune checkpoint proteins, trigger an “off” signal upon binding with the checkpoint proteins, thereby dampening the immune response and preventing the destruction of cancer cells [139]. Immunotherapy drugs known as immune checkpoint inhibitors function by obstructing the binding of checkpoint proteins with their partners, thus thwarting the transmission of the off signal. Consequently, this enables T cells to target and eliminate cancer cells more effectively. Upon encountering cancer cells, cytotoxic T lymphocytes (CTLs) release interferon (IFN)-γ. Following its release, IFN-γ binds to IFN-γ receptors (IFN-γR) present on the surface of tumor cells. This interaction triggers the activation of the JAK-STAT signaling pathway, resulting in the increased expression of programmed death ligand-1 (PD-L1). Subsequently, when PD-1 receptors are blocked, inhibitory signals are transmitted to T cells, impairing their capacity to eradicate tumor cells (Figure 5) [146, 147]. PD-1 is significantly upregulated in thymocytes, NK cells, myeloid dendritic cells, and B and T cells. During inflammatory conditions, PD-L1 and 2 form functional interactions with PD-1 to protect normal tissues. However, this mechanism simultaneously enables tumors to evade immune detection. Therefore, anti-PD-1 agents showed the potential to restore T-cell activation by disrupting this interaction. mAbs targeting ICIs, like PD-1 and its corresponding ligand, have shown significant improvements in extending survival rates across different types of cancers, including advanced GC [148]. Nivolumab and Pembrolizumab are human mAbs of the IgG4 class, specifically engineered to block the PD-1 pathway (See Table 3). CTLA-4 is another critical immune checkpoint molecule found on the surface of T cells. This molecule interacts closely with CD28 and serves a crucial role in downregulating T-cell activation. The CTLA-4 pathway acts in an inhibitory role similar to that of PD-1, when bound by B7–1/2 on an APC [140]. This prevents T cells from binding to the CD28 receptor which is a co-stimulatory molecule on the surface of CD4 cells [151]. Thereby it facilitates the immune escape of tumors.

Figure 5.

Targets and immune checkpoints for GC [145]. Copyright 2021 Elsevier.

Study	Treatment line/Phase	Primary endpoint	Regimen	DCR/ ORR/ (%)
KEYNOTE-059	≥ 3rd line/ II	OS and PFS in PD-L1CPS ≥ 1	Pembrolizumab	−/57.1
KEYNOTE-061	2nd line/ III	OS and PFS in PD-L1CPS ≥ 1	Pembrolizumab	−/46.7
KEYNOTE-062	1st line/ III	OS and PFS in PD-L1CPS ≥ 1	CT + Pembrolizumab	−/64.7
KEYNOTE-164	≥ 2nd line/ II	ORR	Pembrolizumab	57/33
KEYNOTE-177	1st line/ III	PFS and OS	200 mg every 3 weeks	64.7/43.8
CheckMate-142	1st line/ II	ORR	CT	84/69
CheckMate-649	1st line/ III	PS and PFS in PD-L1 CPS ≥ 5	Nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks	−/70

Table 3.

Summarized overview of ongoing trials of checkpoint inhibitor drugs [149, 150].

DCR (disease control rate); PFS (progression-free survival); ORR (objective response rate); CT (chemotherapy).

4.1.1.1 CTLA-4 inhibitors

Antibodies targeting CTLA-4 bind specifically to these small molecules and alleviate T-cell suppression. Key examples approved of anti-CTLA-4 antibodies are Tremelimumab and ipilimumab (Table 3). Ipilimumab obtained FDA approval in 2011 for the management of advanced melanoma. In a clinical study, Ipilimumab showed an objective response rate of 14% in patients with advanced gastric cancer. However, in another trial, Ipilimumab did not increase survival rates when employed as maintenance therapy following first-line chemotherapy for advanced GC or gastroesophageal junction cancer. T Tremelimumab, which acts as a specific CTLA-4 inhibitor is an IgG2 monoclonal human antibody that augments T-cell functionality. In a trial, Tremelimumab administered as a subsequent therapeutic approach showed a median PFS of 1.7 months and a median OS of 7.7 months in patients diagnosed with gastric cancer or gastroesophageal junction cancer following chemotherapy [145, 152, 153].

4.1.1.2 PD-1/PD-L1 inhibitors

Pembrolizumab and Nivolumab have been studied as potential treatments for advanced gastric cancer. In 2017, pembrolizumab was given approval by the Food and Drug Administration (FDA) as a third-line treatment for patients with positive CPS for PD-L1. Nivolumab showed significant survival rate enhancement and received approval as a third-line treatment for GC in Japan. Avelumab did not show significant improvement in overall survival when used as a maintenance and monotherapy treatment following first-line chemotherapy for advanced GC or gastric junction cancer. Overall, PD-1/PD-L1 inhibitors demonstrate clinical effectiveness in the management of advanced GC or gastroesophageal junction cancer., However, the benefits of monotherapy are relatively modest, particularly in later lines of treatment. Despite the approval of anti-PD-1 and PD-L1 therapies as monotherapies and in later lines of treatment, it is not likely that they will emerge as first-line therapies for GC [145, 154, 155].

4.1.1.3 Combinational therapy of Anti CTLA-4 and PD-1

The combination of anti-CTLA-4 and anti-PD-1 antibodies led to the inhibition of epithelial-mesenchymal transition (EMT) and reduced migration and invasion; a notable suppression of cell proliferation and apoptosis induction in MGC-803 and MKN-45 cells. Results from western blot analysis exhibited that this combination reduced the activation of β-catenin, MAPK, and PI3K/AKT signaling pathways. Additionally, in vivo, studies demonstrated that the combination therapy effectively inhibited tumor formation. Furthermore, transfection with si-PD-1 and si-CTLA resulted in significantly decreased levels of CTLA-4 and PD-1 in transcript levels. These findings suggest promising outcomes for the mentioned combination therapy in GC, yet further investigations are required (Table 4) [160].

Drugs(mAb)	Target therapies	VEGFR-2	Ramucirumab
			Apatinib
			Regorafenib
			Lenvatinib
		HER-2	Trastuzumab
			Margetuximab
	ICIs	PD-1	Camrelizumab (SHR-1210)
			Sintilimab
			Nivolumab
			Pembrolizumab
			Toripalimab (ISO01)
			Tislelizumab
		PD-L1	Avelumab
			Atezolizumab
			Durvalumab
			Sugemalimab (CS1001)
		CTLA-4	Tremelimumab
			Ipilimumab

Table 4.

mAb for targeted treatment of GC by inhibiting cell surface receptors [145, 156, 157, 158, 159].

4.1.2 Cellular immunotherapy

The utilization of immune cells as therapeutic interventions for cancer is referred to as cellular immunotherapy. T lymphocytes and NK cells cultivated in vitro are pivotal elements of these therapeutic strategies. These cells can undergo genetic modification to express certain T cell receptors (TCR-T immunotherapy) or chimeric antigen receptors (CAR-T Cell therapy) against desired targets [145].

4.1.2.1 NK cell transfer therapy

NK cells indeed hold a pivotal role in combating tumor cells by hindering the inception and advancement of tumors (Section 1.2.2) [30]. They induce cytotoxicity by release of granzyme and perforin, antibody-dependent cytotoxicity (ADCC), secretion of TNF-α and IFN-γ, and induction of apoptosis through FAS/FASL and TRAIL/TRAILR complex interactions and modulate immune response. However, malignant cells develop mechanisms to evade immune responses. Moreover, NK cells’ quantity and functionality decline as GC advances. Consequently, rectifying NK cell dysfunction may present a promising therapeutic avenue for GC. NK cell adoptive therapy presents a promising therapeutic avenue for gastric cancer. A Phase I clinical trial validated the safety and tolerability of autologous expanded NK cell therapy, which indicates the potential for effective combination treatment with other agents [161, 162].

4.1.2.2 CAR-T cell therapies

Targeted T-cell immunotherapy is the most thoroughly investigated and promising therapeutic pathway in the realm of GC. They have shown impressive results in clinical studies, particularly within hematological malignancies. These cells are genetically engineered to attack cancerous cells. A specific single-chain variable fragment (scFv) binding to a cancerous cell target is essential to engineering CAR-T cells. T cells are subsequently genetically engineered to express a chimeric receptor specifically designed to recognize and attack tumor cells (Figure 5) [163, 164]. Claudin18.2 is a membrane protein specific to the stomach. This molecule has been identified as a promising target in therapeutic approaches in GC as well as other types of cancer. CAR-T cells targeted towards this molecule eradicated gastric tumors in mice without causing unspecific toxicity. The latest clinical findings on GC and pancreatic cancer utilizing CAR-Claudin18.2 T cells have shown promise with a 33.3% overall objective response rate [165, 166]. NK group 2, member D (NKG2D) ligand AKA stress-induced ligand (NKG2DL) is a potential target for GC therapies. This molecule is typically expressed in GC cell lines. NKG2D-CAR-T cells, generated through the modification of CAR-T cells using second-generation CAR vectors, exhibit remarkable anti-tumor efficacy in both animal models and laboratory investigations [167]. HER2 molecule is an abnormally over-expressed molecule in 10–20% of GCs. HER2-CAR-T cells have demonstrated significant and persistent anti-tumor effects against GC cells in laboratory and animal models [168, 169]. Folate receptor 1 (FOLR1) serves as a target molecule that is prominently found overexpressed on the cell surface in more than 30% of GC patients, However, its expression in normal tissue is uncommon. This unique characteristic positions it as a promising target for CAR-T immunotherapy [170]. Prostate stem cell antigen (PSCA), is recognized for its glycosylphosphatidylinositol (GPI) anchored cell surface protein nature and presents as another target for CAR-T cell therapy in GC [171]. Mesothelin (MSLN) has also been considered a cellular target for CAR-T therapy in treating GC. Third-generation CAR-T cells (M28z10T) developed to specifically target MSLN, showed potent anti-tumor activity, underscoring their potential as a promising therapeutic strategy for GC [172].

4.1.2.3 TCR-T immunotherapy

This strategy involves the insertion of TCR genes targeting tumor antigens into the circulating T cells of patients, representing a modified form of adoptive T cell-based cancer immunotherapy. Encouraging outcomes have been observed with this approach across a spectrum of solid tumor types, including multiple myeloma, lung cancer, and synovial sarcoma [173, 174, 175]. Kita-Kyushu Lung Cancer Antigen-1 (KK-LC-1) is frequently identified as a cancer germline antigen in various epithelial cancers, including non-small cell lung cancer, triple-negative breast cancer, cervical cancer, and GC [176, 177]. CT83 expression is remarkably high in GC, and tumor lines positive for CT83 may be recognized by genetically modified T cells with the KK-LC-1 TCR (KK-LC-1 TCR-Ts) in vitro [178]. Another target for TCR-T therapy is potentially the New York esophageal squamous cell carcinoma 1 (NY-ESO-1). Its discovery is rooted in its ability to elicit detectable antibody responses in cancer patients. It is notable that following surgery, those without relapses had sustained reductions in or eradication of the serum levels of NY-ESO-1 antibodies [179]. These results demonstrated the KK-LC-1 TCR-Ts’ encouraging potential for treating GC.

4.1.3 Vaccine treatment

Cancer therapeutic vaccines fall under the umbrella of active immunotherapy, designed to provoke a focused immune reaction against tumor antigens [180]. Peptides, DC, autologous tumor cells, and genetically engineered vaccines are among the vaccines used against cancer. A study evaluated the therapeutic potential of combining adjuvant immunotherapy with chemotherapy in GC patients, employing autologous tumor-derived Gp96 immunization considering that tumor antigens were the initial focus of tumor vaccination research [181]. In the group receiving the vaccine, patients exhibited enhanced rates of disease-free survival and 2-year OS compared to those undergoing chemotherapy alone, standing at 81.9% versus 67.9%. Another investigation, which focused on 9 individuals with advanced GC treated using the HER2/DC vaccine, documented partial clinical remission in a single patient, coupled with a decline in tumor marker levels such as CEA and CA19–9. Furthermore, there were observable anti-tumor effects observed in patients with advanced GC administered Melanoma-associated antigen A3 peptide (MAGE-A3)/DC [182].

Reportedly, 85% of diagnosed GC patients exhibit expression of Lymphocyte antigen 6 complex locus K (LY6K). In six patients with advanced GC, a Phase I clinical trial that investigated the vaccinations with LY6K-derived peptide showed that three out of 6 had more stable disease states and one had a 20% reduction in the size of metastases in their liver [183].

5. Nanomedicine and targeted therapies

Nanomedicine is a crucial tool in cancer management. Nanoparticles (NPs) can enhance the effectiveness of anticancer agents or function as anticancer agents themselves, targeting tumor cells in both active and inactive states based on the tumor type and TME conditions. This overcomes traditional cancer therapy limitations [184].

Polymeric NPs are used as carriers for chemotherapeutic drugs, due to their unique structures that encapsulate drug molecules. They address the limitations associated with these drugs such as instability, low solubility, toxicity, and poor permeability, improving cancer treatment outcomes [185, 186]. Numerous studies have explored the use of polymeric NPs (NPs) loaded with chemotherapeutic drugs like paclitaxel (PCT), doxorubicin (DOX), docetaxel (DCT), 5-fluorouracil (5FU), and other drugs for the treatment of GC. Recently, there has been increasing interest in hybrid drug delivery, which involves delivering two or more chemotherapeutic agents simultaneously, despite their delivery to the tumor site. This approach holds promise as a potent strategy to enhance GC treatment efficacy. However, the most significant challenge remains to achieve a more precise and targeted delivery of drug agents to the tumors’ site, even with NPs. This difficulty arises from the varied physicochemical properties of anticancer agents. For example, researchers have developed NPs based on polyethylene glycol and poly(lactide-co-glycolide) (PEG-PLGA), loaded with 5-fluorouracil (SN-38-5FU@NPs) and irinotecan (SN-38), using the nanoprecipitation technique to improve the effectiveness of GC treatment [187, 188, 189]. Dendritic polymers like Poly(amidoamine) have potential for biomedical applications. PEGylated dendrimers with celastrol are used in GC therapy [184, 190]. Exosomes are nanoscale vesicles that range from 30 to 150 nanometers in diameter. They are secreted by various cell types and hold significant promise as GC therapy. Recent studies shed light on the role and outcome of exosome application in treating GC cell lines. Exosomes have potential as biomarkers for GC diagnosis and as targets for therapeutic approaches [191, 192]. Liposomes are colloidal vesicles made of phospholipids that mimic natural cell membranes. They have a high drug-loading capacity and can deliver hydrophilic and hydrophobic compounds. Liposomes are biodegradable, biocompatible, non-immunogenic, and non-toxic. They are widely used for delivering anticancer drugs in GC treatment [193, 194].

Metallic NPs are used as novel anticancer agents in the treatment of GC. They are produced by capping and reducing metal precursors like zinc acetate dihydrate, copper nitrate, gold halides, and silver nitrate [195]. Metallic NPs can be used alone or with other drugs to achieve better anticancer effects against GC. Silver, gold, nickel oxide, zinc oxide, and cobalt oxide NPs have shown outstanding outcomes against GC cells by augmenting targeting precision, facilitating controlled drug release, supporting imaging modalities, and enhancing gene modification mechanisms [196]. Gold NPs have shown potential as a versatile tool for both diagnosing and treating cancer. Studies have found them to be effective against GC cells while demonstrating good biocompatibility, In AGS cell lines, inhibiting autophagy-related pathways and up-regulating apoptotic signaling [197, 198]. Silver NPs synthesized using eco-friendly methods and natural sources have been shown to significantly inhibit the proliferation of gastric cancer (GC) cells, including the AGS and MNK45 cell lines. This inhibition is achieved by inducing apoptosis, which suggests a promising approach for effective GC therapy [184]. Additionally, nickel oxide and cobalt NPs synthesized through chemical methods displayed cytotoxicity against AGS-GC cell lines in a dose-dependent manner. Nevertheless, nickel oxide and cobalt NPs both exhibited minimal toxicity towards normal fibroblast cells (L929) [197, 198].

5.1 Theranostic NPs

Theranostic NPs are sophisticated nanosystems, that facilitate highly accurate and individualized disease management by amalgamating diagnostic and therapeutic functionality (Figure 6) [200]. Superparamagnetic iron oxide nanoparticles (SPIONs) can be used for magnetic resonance imaging (MRI), while gold nanoparticles (NPs) are well-suited for computed tomography (CT). Therefore, they are commonly used in the construction of theranostic systems. Additionally, some photosensitizers, such as chlorin e6 and IR780, have both tumor-toxic and imaging abilities. This is because they can absorb near-infrared (NIR) light to induce fluorescence and generate reactive oxygen species (ROS) and/or heat [201]. though the structure and assembly of these nano-based theranostic systems can be complex, many have already been reported, demonstrating their potential in treating gastric cancer (refer to Table 5) [200, 214].

Figure 6.

The diagram depicts NPs designed for gastric cancer theranostics. Specifically, it showcases a tumor-targeted and matrix metalloprotease-2 (MMP-2)-activatable nanoprobe (T-MAN). This nanoprobe is developed by modifying Gd-doped CuS micellar NPs with cRGD, covalently. This modification allows for selective entry and accumulation of the nanoprobe in gastric tumors via αvβ3 integrin-mediated active delivery [199]. Copyright 2019 American Chemical Society.

Nanoparticles	Theranostic		Ref.
	Therapeutic strategy	Imaging strategy
ICG-loaded lactosome	PTT	Fluorescence	[202]
Carbon–gold hybrid NPs	PTT	Fluorescence	[203]
RGD-CuS-Cy5.5 NPs	PTT	CT/MRI	[204, 205]
W18O49 NPs	PTT	CT/fluorescence	[204, 206]
PEGPCL-IR780-MET NPs	PTT	PA/fluorescence	[206, 207]
Hyaluronidase-sensitive mesoporous silica NPs	PDT	Fluorescence	[207, 208]
Ternary copper-based chalcogenide nano platform CuS–NiS2 nanomaterials	PTT/PDT	MRI	[209]
Folic acid–sericin–cholesterol/IR780 micelles	PTT/PDT	Fluorescence	[201, 210]
DOX-IR820 NPs	PTT/chemotherapy	Fluorescence	[211]
IR820/paclitaxel/imiquimod/encapsulated thermosensitive liposome	PTT/PDT/chemotherapy	Fluorescence	[201, 212]
PTX-R837-IR820@TSL	PTT/PDT/chemotherapy/ Immunotherapy	Fluorescence	[207]
Cisplatin/ICG loaded PLGA-(DSPE-PEG2000) NPs	Chemotherapy	Fluorescence	[212, 213]
Chlorin e6 functionalized silk fibroin NPs	Chemotherapy	Fluorescence	[208, 210]
Oxaliplatin-Au-Fe3O4-Herceptin NPs	Chemotherapy	MRI	[205, 213]

Table 5.

Nanotechnology-based theranostic(therapeutic/diagnostic) agents for GC.

Photothermal therapy (PTT); Photodynamic therapy (PDT); Arginine-Glycine-Aspartic (RGD).

Xin Luo and et.al developed a nanocarrier system that enhances siRNA delivery using a PD-L1 knock-down system. The system involved creating disulfide-polyethylene glycol-folic acid-conjugated polyethyleneimine coupled with Fe3O4 SPIONs. This approach entailed encapsulating FA-PEG-SS-PEI and SPIONs utilizing a ligand-exchange method, followed by combining this combination with cationic micelles complexed with synthesized siRNA. The product underwent characterization and exhibited excellent contrast for T2-weighted cancer MRI using cellular MRI. PD-L1 siRNAs exhibited notable knock-down of PD-L1, supporting their use as a theranostic approach [215, 216].

6. Other treatments

A notable therapeutic approach involves oncolytic viruses, which possess the ability to selectively destroy tumor cells while leaving healthy cells unharmed [217]. By causing the lysis of tumor cells, oncolytic viruses release TANs as well as tumor-associated antigens, thereby triggering a specific immune response. Rigvir, H101, and T-VEC are among the primary oncolytic viruses utilized in cancer therapy, with Rigvir being the pioneering oncolytic virus approved for clinical use [218].

Employing cytokines and non-specific immune boosters, which can be administered either before or concurrently with antigens to improve the immune response or modify its characteristics without inducing an antigenic response, represents an alternative approach for treating GC. Among these non-specific immune boosters, cytokines and lentinan are commonly employed in clinical settings. Lentinan, a β-1,3-D-glucan, is clinically employed as an immunomodulatory medication for tumor treatment [145].

Combination therapies are often used to achieve better treatment outcomes. For example, combining chemotherapy and trastuzumab in a clinical trial resulted in significantly longer OS rates. Gene therapy in combination with anti-cancer drugs presents a promising opportunity to enhance treatment outcomes [219]. An aptamer-siRNA chimera combined with 5-fluorouracil (5-FU) in a collagen membrane can specifically bind to GC cells, delivering 5-FU to the affected site while suppressing drug-resistant genes [220].

7. Conclusion and outlook

Gastric cancer (GC) is one of the prevalent cancers with poor prognosis. GC is responsible for a significant number of cancer-related deaths across the globe, particularly in its advanced stages (median survival of less than 1 year for metastatic patients). GC is known as a heterogeneous cancer, Furthermore, the biological differences between tumors in Eastern and Western countries have made finding a standard treatment that can include all types of GCs challenging. GC is a multifactorial disease caused by genetic and epigenetic factors; All these factors affect the biological regulatory processes of the cell such as proliferation, differentiation, and cell metabolism. In addition, tumor microenvironment (TEM) in GC differs from normal tissue regarding metabolism. These modifications include the shift from aerobic respiration to glycolysis which leads to lactate production and acidification of the TEM. The TEM contains a diverse range of cells, such as cancer cells, CAFs, pericytes, and other immune cells, and has irregular vasculature. Additionally, it is subject to various mutations. The conditions that were mentioned earlier have led to a lack of response to traditional forms of treatment like surgery, endoscopy, chemotherapy, and radiation therapy. The current treatment methods and the combined treatment of these methods, due to the resistance to the treatment, do not have the necessary effectiveness and are even associated with various side effects; Consequently, new treatment methods with biological approaches are felt more and more as a basic need to develop new treatment strategies. Studying tumor microenvironments and the interplay between cancer cells and immune cells has spurred the development of novel immunotherapy strategies, including the utilization of nanoparticles. A variety of immunotherapies including immune checkpoint inhibitors (CTLA-4 inhibitors،PD-1/PD-L1 inhibitors and Combinational therapy of Anti CTLA-4 and PD-1), cellular immunotherapy (NK cell transfer, TCR-T immunotherapy, and CAR-T cell therapies), cytokines and vaccine therapy have shown promising effects results against GC. NPs are utilized to actively target the tumor site. Moreover, morphological changes in the tumor TEM, such as variations in pH levels and distinct properties of its vessel wall, enable NPs to passively target cancer cells. Further, the usage of theranostic NPs, a combination of therapy and diagnosis, enables better monitoring of response during treatment. These capabilities allow NPs to effectively overcome limitations in GC therapy.

Despite the significant advancements made in the last decade, there are still many challenges to achieving a fully effective method with minimal side effects for the treatment of GC; including reducing the side effects caused by immunotherapy (colitis secondary to immunotherapy with diarrhea, abdominal pain, nausea), toxicity of nanomaterials, etc. In fact, it seems that we cannot eliminate conventional treatment methods, especially surgery and chemotherapy, anytime soon. In the near future, more efforts will be made to fully identify various biological regulatory factors such as ferroptosis, immunological GC, more effective factors on TEM, genomic data of different molecular subtypes, nanomaterials with appropriate biocompatibility and biodegradability. Additionally, scientists will be working to identify reliable predictive factors for early detection which will promise more effective treatment methods.

Author contributions

All authors contributed to the study conception, design, material preparation, data collection, and analysis. The first draft of the manuscript was written by and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.