Table 4 The strengths and weaknesses of the different approaches to reverse ESCC radioresistance and future directions

Immunotherapy

1) It is suitable for ESCC patients with high recurrence rate after surgery or neoadjuvant therapy [193];

2) For metastatic ESCC, treatment combing RT to immunochemotherapy is important for symptom improvement and survival prolongation [194].

1) The evidence of using ICIs in the neoadjuvant setting is lacking;

2) PD-1 is heterogeneously expressed in tumors;

3) The consensus about the PD-L1 assays, OS, PFS and cut-offs are lacking.

1) Validate reliable predictive biomarkers, and then combining biomarkers and intelligent immunotherapy;

2) Reduction in toxicity associated with combination therapy.

Molecular targeted therapy

1) Provide some benefit in an adjuvant setting in patients with locally advanced ESCC to prevent or delay relapse;

2) Dual target (such as EGFR and Wee1) may enhance therapeutic effect [195].

1) It has failed to demonstrate significantly improved OS in clinical trials for patients with recurrent or metastatic ESCC;

2) Intratumorally heterogeneity.

1) Identifying populations susceptible to inhibition by specific molecules;

2) Drugs development based on signaling crosstalk.

Epigenetic modification inhibitors

1) DNMTi and HDACi can be used in combination with antitumor drugs, improving their efficacy and reducing the toxic effects;

2) NcRNAs may serve as some novel prognostic biomarkers;

3) The specific interactions between ncRNAs and ferroptosis [196];

4) Abnormal expression of circRNA could serve as a warning indicator of early tumor diagnosis [197];

5) Nanozymes promote endogenous H₂O₂ catabolism and miRNA delivery, enable efficient effect of RT [176, 198].

1) Using a single inhibitor alone is not enough to fundamentally change the prognosis of cancer patients, and side effects cannot be avoided;

2) The application in clinical settings has been hampered by the lack of specificity, delivery method, and tolerability;

3) The functions of aberrations in histone PTMs machinery remain largely unclear [199].

1) Reducing the toxic effects of drugs;

2) Exploring the relationship and combined efficacy of natural products and DNMTi;

3) Finding a proper approach for the delivery of miRNA to the target area with effectiveness and without being degraded by endogenous RNases [200];

4) Exploring the functions and molecular mechanisms of ncRNAs on ferroptosis.