Comprehensive Integration of Treatments and Therapies for

Esophageal Cancer

Shijun Zheng

Shanghai Starriver Bilingual School, Shanghai, China

Keywords: Esophageal Cancer, m6A Modification, Nanomedicine.

Abstract: Esophageal cancer is one of the most deadly malignant tumors worldwide, with high mortality and few

therapeutic options. It ranks as the eighth most prevalent cancer globally and the sixth largest factor of

common cancer-related death. Epigenetics is of great interest in the adenocarcinoma stage of its development

and undergoing intense investigation as a field for potential translation towards both research and therapy of

esophageal cancer. This focus highlights a methylation of RNA and an epigenetic alteration of N6-

methyladenosine (m6A). Another significant mechanism associated with esophageal cancer is DNA

methylation. Esophageal cancer frequently results in abnormal DNA methylation events, such as

hypomethylation of oncogenes and hypermethylation of tumor suppressor genes. The impact of nutrition on

esophageal cancer both before and after therapy has been studied, much like the previously described

treatment approaches. However, the most cutting-edge approach to cancer treatment is the use of

nanomaterials, which offer therapeutic chemicals or target-specific therapy.

1 INTRODUCTION

Esophageal cancer is among the most aggressive

and lethal cancer withhigh mortality and poor

treatment option globally. Globally it is the 8th

most common cancer and the 6th common cause of

cancer deaths. In terms of results, the 20% 5- year

survival of esophagal cancer was very similar with

the results in the same years reported by the

American National Cancer Institute; however, the

reported 5years survival of esophagal cancer varied

from 5% to 47%. The two histological subtypes of

esophageal cancer (EC)—esophageal squamous

cell carcinoma (ESCC) and esophageal

adenocarcinoma (EAC)—have been shown to differ

in their molecular and aetiological processes. Use

of tobacco, alcohol, obesity, gastroesophageal

reflux disease (GERD), and certain foods and

beverages, like processed meats and hot beverages,

are risk factors (Liang et al. 2023). The outlook for

esophageal cancer remains poor, with current

methods of detection and efficient systemic

approaches both being unavailable, and a five-year

survival rate at less than 20% still remains. This

highlights the need for new approaches to enhance

early diagnosis of disease, treatment response, and

patient prognostication. But when one of the most

common forms and cause of cancer-related death

in the world—esophageal cancer—epigenetics is

being studied in research and therapy. Among these

epigenetic modifications, RNA N6-

methyladenosine (m6A) has attracted great

interest. N6-methyladenosine (m6A) is the most

plentiful known internal modification found in

eukaryotic mRNA and plays roles in RNA

metabolism such as splicing, stability, translation,

and degradation process. Accumulating evidence

indicates that m6A modification deregulation is

linked with various cancers, including esophageal

cancer, and is crucial in tumorigenesis and various

processes of cancer progression, including tumor

growth, metastasis, and resistance to anticancer

therapy. Moreover, new therapeutic targets are

utilizing m6A-modifying enzymes—

methyltransferases (writers), demethylases

(erasers), and binding proteins (readers) that may be

involved in regulating m6A-mediated gene

expression to prevent cancer initiation and

development (Teng et al. 2022).

Esophageal cancer is also closely associated

with DNA methylation, yet another key epigenetic

phenomenon. Abnormal DNA methylation,

including hypermethylation of tumor suppressor

Zheng, S.

Comprehensive Integration of Treatments and Therapies for Esophageal Cancer.

DOI: 10.5220/0014486800004933

Paper published under CC license (CC BY-NC-ND 4.0)

In Proceedings of the 1st International Conference on Biomedical Engineering and Food Science (BEFS 2025), pages 287-294

ISBN: 978-989-758-789-4

287

genes and hypomethylation of oncogenes, is

prevalent in esophageal cancer. In most cases of

tumorgenesis, this process can inactivate some key

genes that are responsible for cell cycle regulation,

apoptosis, and DNA damage repair (Chen et al.

2018). The therapies targeting this epigenetic

aberration in esophageal are forming as a candidate

for therapy such as reverse aberrant methylation

patterns like DNA methyltransferase inhibitors.

Apart from the therapeutic approaches mentioned

previously, the significance of nutrition in the

prevention and treatment of esophageal cancer has

also been described. Not just folates vitamin B12,

well known that molecules speak to some kind of

epigenetic processing, like DNA methylation

therefore as RNA methylation (Meng et al. 2023).

For instance, folate is an essential precursor for

SAM, the main methyl-acceptor in the methylation

pathway. Nutritional interventions can reverse the

normal epigenetic regulation circuit by changing

the availability of methyl donors and other

bioactive compounds that prevent cancer (Miller &

Bozeman 2022). The types of diets or food types

that support a healthy gut microbiome, reduce

inflammation, and starve the potential cancer-

feeders in our gut microbiome still need to be

investigated. Nanomaterials are able to successfully

deliver therapeutic agents in a deliberate and

targeted manner, which indicates a new direction

in the innovative generation of cancer therapy.

Nanomaterials (nanoparticles or nanocarriers) can

be engineered to facilitate the target-specific

delivery of drugs, siRNAs, or epigenetic

modulators to tumor cells, resulting in lower

systemic toxicity and increased treatment efficacy

(Wang et al. 2018).

2 FUNDAMENTAL

MECHANISMS OF RNA N6-

METHYLADENOSINE AND

EFFICACY IN SUPPRESSING

ESOPHAGEAL CANCER

In eukaryotes, N6-methyladenosine (m6A) is an

extensively researched internal RNA alteration. One

of the most prevalent post-transcriptional changes is

adenosine methylation. Site-specific methylation

(m6A) is structured by adding methyl groups (CH3)

to the RNA subunits, generally at the nitrogen-

6position of movements of adenosine, which alters

mRNAs slightly. m6A participates in oncogenetic

signals to promote tumorgenesis, metastasis, and drug

resistance. The "writer" complex that mediates m6A

modification is made up of the methyltransferase

complex METTL3, METTL14, WTAP, and other

associated proteins. While the METTL3 subunit acts

as a catalytic base, METTL14 acts mainly to stabilize

METTL3 and enhance activity. By digitally

demethylating the m6A residues, "eraser" proteins

such as FTO (fat mass and obesity-associated protein)

and ALKBH5 (alkB homolog 5) eliminate m6A

marks. The recognition of m6A by particular binding

proteins, referred to as "readers," which modify the

fates of m6A-modified RNAs, is what drives the

biological activities of m6A in cells. Specifically,

m6A-modified RNA is recognized and bound by the

YTH domain-containing family proteins

(YTHDF1/2/3 and YTHDC1/2). An immune cell

infiltration (ICI) risk model was presented in a work

by Nie et al. that involved mapping the m6A

alteration of single-cell RNA sequencing of

esophageal squamous cell carcinoma (ESCC) H9699

cells (Nie et al. 2023). In this work, Nie et al.

uncovered the distinct m6A modification patterns in

esophageal squamous cell carcinoma (ESCC) cells

and conducted a thorough investigation into the

relationship between tumor heterogeneity and tumor

micro-environmental variables and m6A

modification patterns. Additionally, this method

developed a predictive risk model that uses immune-

related genes linked to m6A to forecast the degree of

immune infiltration and patient prognosis risk. The

model showed the substantial effects of m6A

modifications on immune cell infiltration and

prognostic signature for the progression of ESCC

(Nie et al. 2023). These observations not only shed

light on the molecular mechanisms of RNA

methylation regulation involved in ESCC

pathogenesis but also imply that restoring the m6A

modification levels of methyltransferase may provide

a therapeutic strategy to hinder tumor immune

evasion and enhance clinical outcome in ESCC

patients.

Liang et al. gives another example from the

field in Cancer Letters, which reported the original

research "Methyltransferase-like 3 facilitates

esophageal cancer stem cell properties by

upregulating patched homolog-1 via N6-

methyladenosine methylation" (Liang et al. 2023).

This study provides a thorough analysis of the RNA

methyltransferase METTL3 in driving cancer stem

cell (CSC) properties in esophageal carcinoma. In

their work published in the American Journal of

Physiology-Cell Physiology on September 1, 2023,

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a team of researchers revealed that METTL3-

mediated N6-methyladenosine (m6A) airway

modification upregulated Patched homolog-1

(PTCH1), a critical member of the Hedgehog

signaling pathway, that could lead to induction of

stemness and tumorigenicity (He et al. 2023).

Through additional characterization, molecular and

cellular studies support that METTL3 binds PTCH1

mRNA and promotes its expression by enhancing

m6A methylation and activation of the Hedgehog

signaling pathway. This mechanism promotes

esophageal cancer cell self-renewal and

proliferation and induces chemoresistance.

Depletion of METTL3 in experimental studies

decreases cancer stem cell (CSC) features and

tumor growth, whereas overexpression of

METTL3 is sufficient in enhancing these features.

These findings demonstrate METTL3's

carcinogenic role in fostering stemness and imply

that METTL3 targeting is a viable therapeutic

approach for blocking carcinogenic signaling in

esophageal cancer.

3 APPLICATION OF GENE

METHYLATION AND ITS

RELEVANCE TO

ESOPHAGEAL CANCER

TREATMENT

Gene methylation has been regarded as a key

regulator of gene expression and one of the major

types of epigenetic modification. It can also amplify

or silence the transcription of individual genes.

Aberrant DNA methylation, particularly global

hypomethylation and locus-specific

hypermethylation, is a feature of tumorigenesis. It

contributes to genome instability and transcriptional

repression of tumor suppressor genes and

transcriptional activation of oncogenic pathways in

esophageal cancer. Notably, promoter

hypermethylation of genes involved in cell cycle

regulation, apoptosis, and DNA repair, such as

CDKN2A, APC, and MLH1, are significantly

associated with transcriptional silencing, which is

presumed to promote the malignant transformation

and progression of esophageal squamous cell

carcinoma (ESCC). Methylation profiling has both a

diagnostic and a therapeutic role in esophageal cancer

management. Methylation signatures hold great

potential as biomarkers for early detection and risk

stratification. HoAXA9 and PCDHGA12 were

established as hypermethylation-sensitive assays for

diagnosis in ESCC.

In order to shed light on the part that aberrant

DNA methylation plays in esophageal squamous

cell carcinoma (ESCC), Xi et al. recently published

a paper in Signal Transduction and Targeted

Therapy (Xi et al. 2022). It is done by conducting a

thorough multi-omics analysis that makes it easier

to find clinically significant biomarkers. The

authors described a distinct epigenetic landscape of

ESCC using an integrated approach that included

transcriptomic data, whole-genome bisulfite

sequencing (WGBS; 42 samples), genome-wide

DNA methylation profiling of 425 ESCC patients

and 54 normal controls, and clinical follow-up

information. They discovered 2,735

hypermethylated and hypomethylated (3,879)

genomic regions when comparing tumors versus the

normal tissue, and they varied throughout,

primarily in the promoter regions. These changes

were associated with transcriptional repression of

tumor suppressor genes, including HOXA9 and

PCDHGA12, which disrupted the Wnt/β-catenin

and MAPK pathways to drive tumor progression.

Clinically, the article presented a 12−CpG

methylation−site detection panel that differentiated

ESCC from adjacent normal tissues at high

diagnostic powers (AUC = 0.957−0.985). This

panel was validated on independent patient sets and

in liquid biopsy samples, suggesting its possible

benefit for non-invasive diagnostic strategies. A

prognostic model was then constructed based on 5-

methylation markers (HOXA9, PCDHGA12,

TFPI2, ZNF671, and SIM2) that divided patients

into high- and low-risk groups. Patients that were

classified as high-risk had significantly worse

overall survival than those classified as low-risk

(median overall survival: 23 VS 64 months, p <

0.001). Functional assays confirmed that

demethylating agents like 5-aza-2'-deoxycytidine

reactivated silenced genes (e.g, HOXA9) and

inhibited ESCC cell proliferation. Methylation-

mediated immune evasion strategies in

hypomethylated regions were found to be

associated with immunosuppressive

microenvironments. Thus, the present study

provides the first comprehensive epigenomic map

of ESCC tumorigenesis and identifies numerous

candidate biomarkers for early diagnosis,

prognosis, and pharmacotherapy, highlighting the

translational relevance of targeting DNA

methylation to enhance clinical efficacy in ESCC.

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Using integrated transcriptomic and clinical

data from the TCGA esophageal carcinoma cohort

(184 tumors, 11 normal tissues), Xu et al

conducted systematic analyses of 21 m6A

regulators (writers — e.g., METTL3, WTAP;

erasers— e.g., FTO, ALKBH5; readers— e.g.,

YTHDF2, HNRNPC). Differential expression

analysis revealed that 14 regulators were

significantly dysregulated in tumors compared to

normal tissues (p < 0.05). Six overall survival (OS)-

related regulators (METTL14, YTHDF2, YTHDF1,

HNRNPA2B1, FTO, and ZC3H13) were found

using univariate Cox regression analysis. These

were then further filtered using the multivariate Cox

model to create a four-gene prognostic signature

(YTHDF1, YTHDF2, HNRNPA2B1, and

METTL14). Patients were divided into high- and

low-risk groups according to the median risk scores,

which were generated by weighting the

coefficients. High-risk patients had a considerably

shorter OS than low-risk patients (median OS: 18.6

vs. 47.1 months, p < 0.001), and the signature's

prognostic performance was acceptable (1-year

AUC = 0.72; 3-year AUC=0.69). The multivariate

analysis demonstrated that the risk score was an

independent prognostic factor of overall survival

(OS) (HR = 1.26, 95% CI: 1.12–1.43, p < 0.001),

which was still retained when adjusted for clinical

covariates (age, stage, grade). Functional

enrichment analyses suggested strong correlation

of high-risk scores with tumorigenesis-associated

pathways, including Wnt/β-catenin signaling, RNA

splicing, and metabolic reprogramming. The

prognostic significance of the signature was also

validated independently in another cohort

(GSE53625, n=119) (log-rank p=0.002) (Xi et al.

2022).

4 APPROACHES TO

NUTRITIONAL THERAPY FOR

ESOPHAGEAL CANCER

PATIENTS

Esophageal carcinoma is a malignant tumor with high

morbidity and significant nutrition high-impact

complications generated, thus requiring unique

therapeutic strategies that consider the complex

causal relationship between the progression of the

disease, complications of treatments and nutrient

metabolic disorders. Jordan et al. underscore the

importance of therapies based on nutrition and

omitting foods that cause allergic reactions. This was

underscored in a landmark study published in 2018

entitled Nutritional therapy for Patients with

Esophageal Cancer, which advocated that the impact

of malnutrition on treatment efficacy and clinical

outcomes is significant. They based this conclusion

on a synthesis of data from clinical trials and

observational studies demonstrating that early and

systematic use of nutrition therapy, using enteral

feeding protocols and dietary adjustments, is

associated with reduced postoperative complication

rates, better tolerance of chemotherapy, and improved

survival rates. For instance, by reviewing literature,

they showed that post-esophagectomy infectious

complications were reduced by 22% with

perioperative enteral nutrition (EN) as compared to

parenteral modalities and emphasized the critical role

of gut integrity as a lung-immunological mediator of

gastrointestinal (GI) and immune toxicities.

Furthermore, the authors reduce our attention to the

DE-factochemistry of malnutrition to the recognition

of the therapeutic relevance of organized digital

nutritional evaluation, demonstrating that patients

whose treatment was guided by the Patient-Generated

Subjective Global Assessment (PG-SGA) had 80%

fewer unplanned readmissions. This observation

supports the predictive value of proactive nutritional

surveillance. This review seeks to distill the evidence

supporting the various aforementioned

pathophysiological components along with those

presented by Dr. Bultman and Dr. Marshall to offer a

broad paradigm of nutritional therapy based on the

work of Jordan et al. This framework indicates a need

for multidisciplinary collaborations, a need for

tailored nutrition interventions, and a need for

cancer-targeting agent incursion to concomitantly

address the multimodal needs of esophageal cancer

patients (Jordan et al. 2018).

It is with this in mind that esophageal cancer

represents the rare neoplasm that is potentially

curable, but likely not unless such is accompanied

by the presence of rigorous compliance to an

oncologic dietetic regimen; indeed, in the context

of other esophageal approaches targeting improved

nutrition (i.e., PEG), the emergence of regimented

nutritional protocols in the milieu of CCRT to

esophageal carcinogenic is required to

counterbalance the synergistically deleterious

impact of dysphagia, metabolic stress, and

treatment toxicity. Qiu et al. carried out a

randomized controlled trial (RCT) to assess the

feasibility and effectiveness of whole-course

nutrition management (WCNM), a multimodal

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method incorporating proactive assessment,

tailored dietary planning, and therapeutic

monitoring in 120 patients with locally advanced

esophageal squamous cell carcinoma (Qiu et al.

2020). A total of 120 participants were randomized

to either the control group, which received

conventional care (n = 60), or the Whole-Course

Nutrition Management (WCNM) group (n = 60).

Anthropometric (BMI, mid-arm circumference),

biochemical (serum albumin, prealbumin), and

Patient-Generated Subjective Global Assessment

(PG-SGA) parameters are used to determine the

baseline nutritional status. Moreover, surpluses and

deficiencies in body composition were evaluated

using BIA (Bioelectrical Impedance Analysis).

During the formal treatment phase, caloric and

protein needs were assessed by means of indirect

calorimetry, with targets set at 25–30 kcal/kg/day

and 1.5 g of protein/kg/day, respectively. High-

energy oral nutritional supplements (ONS) were

used to optimize daily intake, and modified-texture

diets (e.g., puréed or liquid formulations for

patients with dysphagia) and intermittent enteral

nutrition (EN) via nasogastric tubes were

prescribed for those whose oral intake compliance

was less than 60% (67% of patients).

Weekly evaluations were performed during the

intensive treatment cycles to monitor weight

changes and gastrointestinal toxicity (CT CAE

v4.0), and metabolic parameters. Issues like

anorexia, mucositis, or dehydration were handled

adaptively. In actual fact, by far the most thorough

assessment, the WCNM group had much greater

maintenance of lean body mass (LBM) (+3.2 kg and

2.1 kg; p=0.01) and serum albumin levels (35.2 g/L

and 30.1 g/L; p=0.003) at the end of CCRT. They

also achieved more completed CCRT cycles

(81.7% vs. 63.3%; p=0.02) and experienced less

grade 3 esophagitis (18.3% vs. 35.0%; p=0.04). In

a 12-month follow-up, the authors observed better

PFS in the WCNM group (HR: 0.62; 95% CI: 0.41-

0.93; p=0.02), and this was explained by

immunological resilience and less treatment

suspension. Motivated by conclusions, the WCNM

framework utilizes anticipatory nutritional support

to alleviate the catabolic cascades driven by

CCRT. Preservation of mucosal integrity alongside

reductions in cytokine-driven muscle wasting is

achieved by the establishment of WCNM-derived

anabolic substrates (e.g., branched-chain amino

acids, omega-3 fatty acids) and oxidative stress. In

addition, earlier initiation of EN maintains the gut-

associated lymphoid tissue (SALT) activity and

decreases bacterial translocation and associated

systemic inflammation. The findings underscore the

need for nutrition therapy to be incorporated into

oncology care pathways. This paradigm shift in the

management of nutrition from reactive management

to proactive behavioral interventions—such as real-

time adaptation to toxicities—corresponds with

emerging evidence that optimum nutrition

influences therapeutic efficacy and survivorship in

esophageal cancer. WCNM’s Multidisciplinary

Approach in both Oncologic Workflows and

Nutritional Interventions Future clinical protocols

must adopt the interdisciplinary framework

established by WCNM, integrating dietitian-led

clinical interventions within oncologic workflows

to expand the standards of care delivery (Qiu et al.

2020).

5 TARGETED

NANOMATERIALS FOR

ESOPHAGEAL CANCER

THERAPY

Nanomaterials are utilized to deliver therapeutic

agents for the treatment of esophageal cancer (EC),

achieving efficiency against distinct biological

barriers using high surface-area-to-volume ratios,

tunable surface chemistries, and responsive

behaviors, particularly for the size range of 1–100

nm. Both passive and active targeting mechanisms

are at the core of their design. Passive targeting

utilizes the leaky structure of tumor vasculature by

facilitating the specific accumulation of

nanoparticles (NPS) in tumor tissues via the enhanced

permeation and retention (EPR) effect. In this

method, NPS are covered with ligands, which can

include chemicals, peptides, and antibodies that can

bind to certain biomarkers on the surface of

esophageal tumor cells such as EGFR, HER2, and

FR. Xiao et al. also emphasize that dual-targeting

delivery systems, which combine both strategies,

achieve greatly improved drug bioavailability and

cellular uptake and elicit much lower toxicity to

healthy tissues. This is a critical breakthrough for the

treatment of esophageal cancer tumor tissues that are

anatomically complex and heterogeneous (Xiao et al.

2023). Nanomaterial platforms for efficient

electrocution therapy in Xiao’s study include: (1)

Lipid-Based Nanoparticles: Liposomes are a

natural delivery system providing a basophilic

environment for hydrophobic chemotherapeutics

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(e.g. paclitaxel) and nucleic acids. Solid lipid

nanoparticles (SLNs) are the next generation of lipid

nanoparticles. Xiao et al. highlight how

functionalization of these nanoparticles with anti-

CD44 antibodies allows for targeting of cancer stem

cells in esophagus cancer, which leads to improved

tumor penetration and lower rate of recurrence (Xiao

et al. 2023). (2) Polymeric Nanoparticulates: LPGA

and chitosan-based nanoparticles are used for

controlled release of drugs and to provide adherence

to the mucosa. The latter property increases the lumen

residence time and thus improves localized delivery

of agents like 5-fluorouracil, as noted by Xiao et al.

(3) Inorganic Nanomaterials: Inorganic

nanoparticles such as gold nanoparticles (AuNPs)

and iron oxide nanoparticles (IONP) are commonly

used as both diagnostic and therapeutic modalities.

For example, AuNPs enable photothermal therapy

(PTT) upon exposure to near-infrared (NIR) light,

while IONPs can be used for MRI-guided

hyperthermia, as demonstrated in preclinical studies

of esophageal cancer. (4) Stimuli-Responsive

Nanosystems: Xiao et al. discuss the emergence of

nanoparticles that trigger payload release in response

to cues derived from the tumor microenvironment

(e.g., acidic pH, matrix metalloproteinases [MMPs])

or external stimuli (e.g., light, magnetic fields). It

enables the targeted release mechanism, decreasing

off-target toxicity (Xiao et al. 2023).

To overcome these obstacles, the advent of

nanomedicine has proposed a novel paradigm

combining diagnostic with therapeutic functions. Li

et al. suggested that they will discuss the recent

advances in nanomedicine to combat hepatocellular

carcinoma (HCC) and delineate the

biophysicochemical mechanisms by which

innovative materials can allow precision, reduce

off-target effects, and the capacity to overcome

biological barriers (Li et al. 2022). Efficacy of

Nanomedicine in Esophageal Cancer (EC)

Nanomedicine delivery systems mainly consist of

targeted delivery mechanisms, which can be

divided into passive targeting and active targeting

delivery systems. Passive targeting is based on the

enhanced permeability and retention (EPR) effect,

which allows nanoparticles (NPs) to selectively

accumulate in solid tumors due to leaky vasculature

and dysfunctional lymphatic drainage. Active

targeting increases specificity via functionalization

of NPs with ligands including antibodies, peptides,

or aptamers that interact with EC-related markers

such as epidermal growth factor receptor (EGFR),

human epidermal growth factor receptor 2 (HER2),

and Claudin 18.2. Li et al. report that dual-targeted

platforms driving bioaccumulation maximize

cellular uptake by exploiting both EPR-dependent

aggregation and ligand-receptor (LR) interactions

(Li et al. 2022). By way of example, anti-EGFR-

conjugated NPs have exhibited deep penetration

into tumors in preclinical models and inhibited

metastatic spread while sparing normal esophagus

tissues from injury. Simultaneously,

multifunctional nanoplatforms for EC diagnosis

and therapy are developed and improved.

Polymeric nanoparticles are suitable materials for

the controlled delivery of chemotherapeutics (e.g.,

paclitaxel or 5-fluorouracil) or poly (lactic-co-

glycolic acid) (PLGA), whereas inorganic

nanomaterials (e.g., gold or iron oxide

nanoparticles) are used for both imaging and

therapy. Nanogold is a theranostic that can be

employed in PTT processes using NIR irradiation;

its strong photoacoustic imaging capability makes

it also an excellent contrast agent.

pH-sensitive covered doxorubicin-loaded MSNs

have also been demonstrated to not only improve

solubilization but also release the payload once

within the acidic TME, thus helping reduce the

effect of drug resistance. Such advances reflect the

continued transition to personalized, image-guided

treatments that are more rational given the

molecular heterogeneity of esophageal cancer (EC).

But major translational barriers persist. Li et al.

established the overwhelming extracellular matrix,

hypoxic TMEs, and heterogeneity of receptor

expression in patients as critical barriers to leading

to nanomedicine clinical efficacy (Li et al. 2022).

In addition, the need for extensive preclinical

validation due to concerns of long-term

biocompatibility, scalability of synthesis, and

regulatory issues further complicates translation to

clinical applications. To overcome such limitations,

they suggest utilizing patient-derived xenograft

(PDX) models and organoid-based drug testing

platforms to better mimic the pathophysiology of

human EC. According to a study published in 2017,

the ZD1-D/siCTLA4 targeted local delivery of

cisplatin, a small molecule anti-cancer drug, can

inhibit immune checkpoint pathways and break

immune tolerance with immune checkpoint

inhibitors, which is presumably achieved by this

combinatorial way, namely, co-delivery of

chemotherapeutics with immune checkpoint

inhibitors or small interference RNA (siRNA)

against oncogenic pathways to overcome the

resistance mechanism and improve the efficiency of

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the anti-tumor therapy (Li et al. 2022).

Nanomedicine, therefore, glimmers a new dawn in

esophageal cancer (EC) intervention, where

diagnostic accuracy and targeted delivery would

gradually be replaced by multifunctionality at the

nanoscale to address the bottlenecks in

conventional therapies. Li et al. point out future

work will have to be interdisciplinary in order to

inform best practices in material design, safety

profile validation, and regulatory strategy. Next-

generation nanoplatforms can revolutionize EC

therapy due to their capability to harness advances

in biomarker discovery and nanotechnology, which

lead to improved early detection, better therapeutic

precision, and higher survival rates (Li et al. 2022).

6 CONCLUSION

Esophageal cancer (EC) is a highly aggressive

malignancy with high morbidity and mortality rates.

It is still an important global health problem because

of its rapid evolution and frequent late diagnosis.

Standard of (SoCs) for early dependent stage and

progressed EC based on recent molecular

information, therapeutic medicines approved for

different signs of cancer, and supportive

consideration measures at that point have radically.

Over can totally change the computational

administration of EC. But these strategies may not be

enough to conquer all the obstacles presented by this

disease. RNA N6-methyladenosine (m6A)

modifications have emerged as important

modulators of the gene expression alterations that

arise during EC suppression.

More specifically, m6A regulates post-

transcriptional gene expression in RNA stability,

splicing, translation, and so on. Of note, both the

methyltransferase METTL3 and the demethylase are

implicated in EC dysfunction, thereby presenting

competitive therapeutic avenues through which

tumor suppressor pathways can be re-established.

Additionally, abnormal DNA methylation—

particularly hypermethylation of tumor suppressor

gene promoters such as CDKN2A and APC—can be

utilized not only as a biomarker for early detection but

also as a target for demethylating agents (e.g.,

azacitidine). While m6A modulation can enhance

tumor sensitivity to epigenetic therapies by repressing

target gene expression, off-target effects and limited

mechanistic understanding of these therapeutic

strategies remain significant barriers to their clinical

implementation. Epithelial-mesenchymal transition

(EMT) is a hallmark of malignancy. Such

functionalized nanoparticles allow targeted delivery

of chemotherapeutic drugs (e.g., paclitaxel) or

siRNA directly to a tumor via ligand-receptor

interactions (e.g., Incorporating this strategy

improves drug bioavailability, reduces systemic

toxicity, and circumvents multidrug resistance.

Synergy can also be achieved through the application

of photothermal and redox-responsive

nanomaterials. However, the scalability of this

approach, its biocompatibility, and its long-term

safety need to be thoroughly assessed through clinical

evaluation. Nutritional therapy, including high-

protein oral supplements, enteral feeding in

gastrostomy tubes, and optimization of

micronutrients (e.g., zinc, selenium), alleviates

cachexia and restores immune function. In particular,

a tailored dietary plan (i.e., developed according to a

patient’s goals and treatment phases) ensures

adequate postoperative recovery and increases

chemoradiation resistance. However, differences in

socioeconomic status and gastrointestinal

complications may restrict adherence to the diet.

Managing esophageal cancer (EC) remains a major

clinical challenge, despite numerous advances.

Nonspecific symptoms and lack of effective

biomarkers make early detection challenging.

Biologically, tumor heterogeneity is a challenge in

incorporating standardized therapies, which

highlights the need for biomarkers for patient

stratification. Epigenetic and RNA-modulating

therapies can be non-specific and activate off-target

genes. The translation of nanomaterials is also

bottlenecked by regulatory barriers and

manufacturing complexities. Second, nutritional

support should be integrated into oncological care,

which can often be neglected in resource-poor

settings due to the need for multidisciplinary

collaboration.

A singular multidisciplinary approach—blending

molecular biology, nanotechnology, and integrative

holistic supportive care—is paramount. Liquid

biopsies and AI-informed diagnostics might enable

earlier detection. Combination therapies, such as

m6A inhibitors + immunotherapy, are investigated in

clinical trials and have the potential for synergistic

efficacies. Finally, despite the promising perspectives

opened up by the convergence of molecular biology,

nanotechnology, and nutritional science towards

achieving a new field in the context of a better

understanding of EC, several biological and systemic

issues that can compromise the treatment outcome

(survival and quality of life) for patients all over the

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world remain to be solved before this new treatment

modality can be introduced.

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