{"doi":"10.1002/ctd2.160","title":"R(h)oad to antitumour therapy","abstract":"Autophagy, an evolutionarily intracellular degradation catabolic process maintains cellular homeostasis during stress conditions to recycle nutrients from damaged organelles.1, 2 Importantly, although autophagy plays a dual role in tumour promotion and suppression in many cancers, inhibition of autophagy plays a vital role in cancer immunotherapy. Studies have shown that altering the autophagic process by inhibiting or inducing can promote the effectiveness of immunotherapy.3, 4 Immunogenic cell death (ICD) is a distinctive immune response induced by anticancer chemotherapeutics resulting in cell death induced by cellular stress and eventually release of damage-associated molecular patterns.5, 6 Pharmacology-inducing ICD activates autophagy in tumour cells, which together with radiotherapy/chemotherapy boosts efficacy by promoting ICD.7 In their letter to the editor, Yang et al. propose that pharmacological enhancement in the autophagy process can be effective in boosting anticancer immune responses to ICD drugs.8, 9 They propose that ginsenoside Rh2 (G-Rh2) heightened the mitoxantrone (MTX)-induced ICD including adenosine triphosphate (ATP) release increase, discharge of high mobility group box 1 (HMGB1) and repositioning of calreticulin (CALR) to the membrane enhancing anti-tumour immune responses (Figure 1). G-Rh2 are ginsenosides, the main components from ginseng and proved to have pharmacological anti-cancer capabilities, inducing autophagy by activating transcriptional factors EB (TFEB) and E3 (TFE3) which adds to the collaborative effect of G-Rh2 that together with the chemotherapy drug MTX activates ATP release.9, 10 Yang et al. showed that in U2OS cells (human bone osteosarcoma epithelial cells) G-Rh2 is responsible for upregulating LC3-II levels, which is further enhanced by the addition of CQ lysosomal inhibitor, proving that G-Rh2 promotes autophagy in osteosarcoma epithelial cells. They went beyond and using immunofluorescence and western blotting to determine that G-Rh2 increases the expression of TFEB and TFE3. Moreover, once these genes are knockdown Rh2-mediated effect is blocked. The authors also demonstrated that G-Rh2 can induce ICD on different concentrations of MTX, an anti-cancer chemotherapy drug. To better understand how G-Rh2 induces ICD, they showed that low concentrations of MTX together with G-Rh2, decrease intracellular ATP levels (preferentially released); however, once ATG5 gene was knockdown there was a clear inhibition of autophagy. ATG5 is required for autophagy and it is vital for the formation of autophagosomes,11 thereby establishing that autophagy if the fundamental mechanism that needs to be activated for successful cancer therapy using chemotherapy drug. Interestingly, Yang et al. also determined that when inhibiting endoplasmic reticulum (ER) stress with the addition of 4-phenylbutyric acid, leads to the relocation of CALR on the cell surface, and the release of HMGB1 increasing antitumour effects. This is consistent with previous findings where induction of ER stress leads to alarmin release and cell death12; however, the reason why ER stress is induced upon the addition of G-Rh2 needs to be established. The unfolded protein response (UPR) main purpose is to restore the ER's homeostasis, however, continual UPR activation can trigger cell death pathways.12, 13 Additionally, they suggested that the combination of G-Rh2 and MTX also induces apoptosis and it is increased by the lysosomal inhibitor CQ, indicating that the apoptosis pathway is also implicated in antitumour activities. Moreover, Z-VAD-FMK, an apoptosis inhibitor, constraints apoptosis by G-Rh2 together with MTX, but neither influenced intracellular ATP levels, nor cell surface CALR exposure. This is interesting, and although the authors assume that maybe the anti-tumour effect of G-Rh2 plus MTX is activated by ICD rather than apoptosis, this needs to be further evaluated to differentiate between ICD and apoptosis. One possib","journal":null,"year":2022,"id":313692,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9511,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":275821,"name":"Bibhuti B. Mishra","orcid":"0000-0002-7203-1653","position":1,"is_corresponding":false},{"id":342725,"name":"Brij B. Singh","orcid":"0000-0003-0535-5997","position":2,"is_corresponding":false},{"id":518136,"name":"Viviane Nascimento Da Conceicao","orcid":"0000-0002-0589-1493","position":0,"is_corresponding":true}],"reference_count":17,"raw_metadata":null,"created_at":"2026-07-19T00:33:48.490749Z","pmid":"37790799","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}