INTRODUCTION
In 2011, the United States Food and Drug Administration first approved the immune checkpoint inhibitor (ICI) ipilimumab, a monoclonal antibody that inhibits cytotoxic T-lymphocyte-associated protein 4 (CTLA-4; CD152), for treating metastatic melanoma. 1 Following that, ICIs have rapidly expanded their indications across various cancer types and have fundamentally changed the paradigm of existing cancer treatments. 2 Currently, ICIs selectively target and inhibit either CTLA-4 or the programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis. 3 This inhibition serves to potentiate the host immune response, thereby enhancing the anti-neoplastic effects. 4 However, ICIs can also induce inflammatory adverse events caused by autoimmunity, which are referred to as immune-related adverse events (irAEs). Moreover, irAEs can affect any organ and result in various morbidities, leading to prolonged delays or discontinuation of cancer treatment. The exact etiology of irAEs remains elusive, with increased T-cell activity against healthy tissues, elevated levels of autoantibodies, and inflammatory cytokines suggested as potential causes. 5 , 6 Among irAEs, ICI-related diarrhea/colitis is reported in approximately 15% to 30% of cases, ranking as the second most common site affected by ICIs following dermatologic involvement. 7 ICI-related diarrhea/colitis can lead to various clinical outcomes, including severe cases necessitating the postponement of the ICI administration. Consequently, this may delay therapeutic interventions for the underlying malignancies.
DIAGNOSIS OF ICI-RELATED DIARRHEA/COLITIS
In patients receiving ICI treatment, the manifestation of symptoms including diarrhea, abdominal discomfort, hematochezia, and mucoid stools warrants clinical suspicion of ICI-related colitis. Although the median onset typically occurs six to eight weeks after initiating anti-CTLA-4 therapy 8 and two to six months following anti-PD-1/anti-PD-L1, 9 , 10 the onset times can vary. In addition, when two ICIs are used in combination, the onset time can be shortened. 10 For patients suspected of having ICI-related diarrhea/colitis, the first step is to assess symptom severity. Supportive care and symptomatic treatment are considered for grade 1 symptoms based on the common terminology criteria for adverse events (CTCAE, Table 1 ), 11 allowing continuation of ICI therapy. Among the reported analyses of ICI-related diarrhea/colitis, grade 1 incidents range from 12% to 40%, grade 2 from 32% to 47%, and grades 3 and 4 together make up approximately 32% to 56% of cases. 12 - 15 These proportions should be interpreted with caution because grade 1 symptoms are likely to be omitted. For grade 2 or higher symptoms, discontinuation of ICI therapy and initiation of further assessments are imperative. This process includes microbiological testing for infectious causes, including Clostridioides difficile and cytomegalovirus, along with recommended stool lactoferrin or calprotectin tests, and thyroid function tests. In patients presenting with systemic symptoms such as fever or severe abdominal pain, appropriate imaging studies such as computed tomography are advisable. Importantly, an endoscopic evaluation should be considered when ICI-related diarrhea/colitis is suspected to differentiate it from other colitis etiologies and assess its severity ( Fig. 1 ). 16 - 18 Novel modalities such as transabdominal ultrasonography (US) and artificial intelligence-assisted endoscopy are being recognized for diagnosing intestinal diseases. 19 , 20 According to a prospective study by Sakurai et al., 21 transabdominal US was used to evaluate ICI-related colitis, displaying results similar to those observed in ulcerative colitis (UC).
Table 1.
Common terminology criteria for adverse events (CTCAE) grades ver. 5.0 11
ADL, activity of daily living.
| Grade | Diarrhea | Enterocolitis |
| 1 | Increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline | Asymptomatic; clinical or diagnostic observations only; intervention not indicated |
| 2 | Increase of 4–6 stools per day over baseline; moderate increase in ostomy output compared to baseline; limiting instrumental ADL | Abdominal pain; mucus or blood in stool |
| 3 | Increase of ≥7 stools per day over baseline; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self-care ADL | Severe or persistent abdominal pain; fever; ileus; peritoneal signs |
| 4 | Life-threatening consequences; urgent intervention indicated | Life-threatening consequences; urgent intervention indicated |
| 5 | Death | Death |
DISTRIBUTION OF INTESTINAL INFLAMMATION IN ICI-RELATED COLITIS
ICI-related colitis predominantly manifests as extensive colitis, ranging from 23% to 86%. 12 , 14 , 22 - 26 According to the largest cohort study by Abu-Sbeih et al., 12 23% of the participants exhibited extensive colitis. Left-sided colitis is the second most prevalent type, with a reported frequency of 31% to 44%. 12 , 14 , 15 Right-sided colitis is less common, accounting for only 3% to 8%, 12 , 14 , 23 with ileitis constituting a low proportion, ranging from 2% to 16% ( Table 2 ). 12 , 14 , 15 , 22 - 26
Table 2.
Distribution of intestinal inflammation in immune checkpoint inhibitor-related colitis assessed by lower gastrointestinal endoscopy
ICI, immune checkpoint inhibitor; m/c, most common; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; n/a, not available; PD-1, programmed cell death protein 1; NSCLC, non-small cell lung cancer; PD-L1, programmed cell death-ligand 1; RCC, renal cell carcinoma.
| Study | Year | No. of patients | Type of malignancy | Target of ICI | Proportion of extensive colitis (%) | Distribution of inflammatory lesions excluding extensive colitis |
| Marthey et al. 24 | 2016 | 39 | Melanoma (m/c, 90%), prostate cancer, lung cancer | CTLA-4 | 66 | n/a |
| Coutzac et al. 22 | 2017 | 33 | Metastatic melanoma, Hodgkin’s lymphoma, prostate cancer, NSCLC | CTLA-4 (82%), PD-1 (18%) | 86 | Ileum (7%), left colon (4%), rectum (4%) |
| Abu-Sbeih et al. 12 | 2018 | 182 | Melanoma (m/c, 42.3%), solid malignancy (51.1%), hematological malignancy (6.6%) | CTLA-4 (39%), PD-1/PD-L1 (36.8%), combination (24.2%) | 23 | Involvement of terminal ileum (6%), right colon only (3%), left colon only (31%), normal (37%) |
| Geukes Foppen et al. 23 | 2018 | 92 | Melanoma (87%), NSCLC (13%) | CTLA-4 (56%), PD-1 (23%), combination (21%) | 68 | Isolated right colon (8%) |
| Yamauchi et al. 25 | 2018 | 3 | NSCLC | PD-1 | 67 | n/a |
| Wang et al. 15 | 2018 | 53 | Melanoma (70%) | CTLA-4, PD-1, CTLA-4+PD-1 | n/a | Among patients with inflammation on endoscopy: left colon (43%), left and right colon (40%) ileocolonic (14%), ileum only (2%) |
| Yanai et al. 26 | 2020 | 11 | Multiple myeloma (55%), RCC (27%), NSCLC (18%) | PD-1 or CTLA-4+PD-1 | 27 | n/a |
| Kou et al. 14 | 2023 | 25 | Melanoma (20%), gastric adenocarcinoma (20%) | PD-1/PD-L1, PD-1+CTLA-4 | 52 | Right colon only (4%), left colon only (44%), involvement of terminal ileum (16%) |
Sigmoidoscopy can be performed more frequently and promptly than colonoscopy as the procedure does not require bowel preparation. According to a systematic review by Wright et al., 27 over 98% of patients with ICI-related colitis exhibited left colon involvement when histological assessment was performed in addition to endoscopic findings. De Silva et al. 13 conducted another study involving 47 patients with ICI-related colitis who underwent colonoscopy. Histological analysis revealed the presence of ICI-related colitis across all colon segments in 35 patients (74.5%), with no cases of isolated proximal colon involvement. Given its superior convenience compared to colonoscopy, sigmoidoscopy with biopsies is recommended as the first-line diagnostic tool for ICI-related colitis according to recent guidelines. 17 However, considering the reported proportion of right-sided colitis and isolated ileitis, patients with persistent symptoms despite normal sigmoidoscopic findings are advised to undergo colonoscopy when no contraindications exist for the procedure.
ICI-RELATED ENDOSCOPIC FINDINGS
The ICI-related endoscopic findings are summarized in Table 3 . Consistent findings were observed across numerous studies, describing features such as loss of vascularity, erythema, edema, granular appearance, friability, and erosions/ulcers. 12 , 13 , 15 , 23 - 26 , 28 - 31 These findings exhibit similarities to the endoscopic characteristics of inflammatory bowel disease (IBD), making it challenging to differentiate between ICI-related colitis and IBD. The aforementioned similarities underscore the importance of thorough clinical, endoscopic, and histological assessments to accurately distinguish between the two conditions. The frequency of ulcers varies between 32% and 79%. 15 , 23 , 24 , 26 The proportion displaying normal mucosa in endoscopic findings ranges from 19% to 37%, 12 , 15 , 26 , 28 indicating the necessity of conducting biopsies for normal mucosal lesions when ICI-related colitis is suspected. Representative images of the endoscopic findings of ICI-related diarrhea/colitis are displayed in Figure 2 .
Table 3.
Immune checkpoint inhibitor-related endoscopic findings
ICI, immune checkpoint inhibitor; UGI, upper gastrointestinal; LGI, lower gastrointestinal; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; n/a, not available; m/c, most common; NSCLC, non-small cell lung cancer; PD-1, programmed cell death protein 1; UC, ulcerative colitis; PD-L1, programmed cell death-ligand 1; CD, Crohn disease; RCC, renal cell carcinoma.
| Study | Year | No. of patients | Type of malignancy | Target of ICI | UGI finding | LGI findings |
| Verschuren et al. 31 | 2016 | 25 | Prostate cancer, melanoma | CTLA-4 | n/a | Loss of vascular pattern (100%), granulation (100%), erythema (84%), friability (64%), swollen or blunt rectal valves (76%), ulceration (68%) |
| Marthey et al. 24 | 2016 | 39 | Melanoma (m/c, 90%), prostate cancer, lung cancer | CTLA-4 | Esophageal ulcer (4.5%), gastritis (40.9%), erosive duodenitis (9.1%) | Most severe lesions identified: ulcer (79%), erosion (13%), erythema (8%) |
| Kubo et al. 29 | 2017 | 1 | NSCLC | PD-1 | n/a | Edema, erythema, exudate, sequential loss of vascular pattern: mimicking UC |
| Gonzalez et al. 28 | 2017 | 20 | Melanoma (60%) | PD-1/PD-L1 | Stomach: normal mucosa (33%), erythema, erosion | Normal mucosa (35%), erosion, friability, granularity |
| Lung cancer (25%) | Duodenum: normal mucosa (50%), erythema, erosion | |||||
| Abu-Sbeih et al. 12 | 2018 | 182 | Melanoma (m/c, 42.3%), solid malignancy (51.1%), hematological malignancy (6.6%) | CTLA-4 (39%), PD-1/PD-L1 (36.8%), combination (24.2%) | n/a | Normal mucosa (37%) |
| CD-like pattern (34%), and UC-like-pattern (66%), if lesions were detected | ||||||
| Geukes Foppen et al. 23 | 2018 | 62 | Melanoma (87%), NSCLC (13%) | CTLA-4 (56%), PD-1 (23%), combination (21%) | n/a | Ulcer (32%), loss of vascular pattern (80%), friability (81%), granular pattern (75%), mucopurulent exudate (62%) |
| Wang et al. 15 | 2018 | 53 | Melanoma (70%) | CTLA-4 (69.8%), PD-1 (13.2%), CTLA-4+PD-1 (17.0%) | n/a | Normal mucosa (19%), ulcer (40%), nonulcerative inflammation (42%), diffuse or patchy erythema, inflammatory exudate, loss of vascular pattern, aphtha, edema, friability, erosion |
| Yamauchi et al. 25 | 2018 | 3 | NSCLC | PD-1 | n/a | Reddish, edematous mucosa with increased mucous exudate and loss of vascularity |
| Yanai et al. 26 | 2020 | 11 | Multiple myeloma (55%), RCC (27%), NSCLC (18%) | PD-1 | n/a | Normal mucosa (36.4%), erythema (85.7%), granularity (100%) erosion (71.4%), ulcer (57.1%) |
| De Silva et al. 13 | 2022 | 51 | Melanoma (19.6%), RCC (9.8%), colon adenocarcinoma (7.8%), breast cancer (7.8%), others | PD-1 (58.7%), CTLA-4+PD-1 combination (19.6%) | n/a | Edema, erythema, ulceration, pseudomembranous colitis |
| Parente et al. 30 | 2022 | 19 | Melanoma (47.6%), RCC (19.0%), NSCLC (14.3%) | PD-1/PD-L1 (81.3%), CTLA-4 (14.3%), combination (PD-1+CTLA-4, 4.8%) | Esophageal exudate, gastric erythema, duodenal erosion | Deep ulceration, fistula, erythema, friability, reduction of vascular pattern, exudate, mucosal hemorrhage, erosions |
Verschuren et al. 31 reported that all ICI-related endoscopic findings demonstrated a loss of vascular patterns and granulation. Erythema was observed in 84% of the patients. In the study by Marthey et al., 24 which analyzed patients treated with CTLA-4 targeting ICIs, ulceration was the most severe endoscopic finding in 79% of patients. Geukes Foppen et al. 23 summarized 92 endoscopic findings from 62 patients, in which ulcers were observed in 32% of cases. Inflammation was observed as a continuous pattern on most endoscopies (79%). Frequently observed features included loss of the vascular pattern (80%), friability (81%), granular pattern (75%), and mucopurulent exudate (62%). Wang et al. 15 classified the endoscopic findings of ICI-related colitis as colitis with ulceration, non-ulcer inflammation, and normal lesions, accounting for 40%, 42%, and 19% of cases, respectively. The endoscopically observed inflammation in this study exhibited a diffuse pattern (51%), followed by patchy (42%) and segmental (7%) patterns. The largest cohort study encompassing ICI-related endoscopic findings was performed by Abu-Sbeih et al. 12 In this study of 182 patients, individuals exhibiting abnormal lesions were categorized according to their resemblance to IBD. The Crohn disease (CD)-like group comprised 34%, whereas the UC-like group comprised 66%.
Several studies have attempted to analyze the association between these endoscopic findings, symptom severity, and patient prognosis. In the study by Abu-Sbeih et al., 12 the group demonstrating high-risk endoscopic features (ulcers deeper than 2 mm, larger than 1 cm, and extensive colonic involvement) was associated with the usage of infliximab/vedolizumab due to refractoriness to corticosteroid, along with frequent and prolonged hospital stays. Wang et al. 15 classified patients with ICI-related diarrhea or colitis into two groups based on the presence of ulcers. The group with ulcers had a significant proportion of steroid-refractory cases (62% vs. 31%) and a greater incidence of grade 2 symptoms or higher diarrhea (100% vs. 79%). In a study by Geukes Foppen et al., 23 the severity of endoscopic lesions was evaluated using the Mayo Endoscopic Score. No correlation was observed between the severity assessed using the Mayo endoscopic score and the grade of diarrhea. However, patients with greater endoscopic severity and pancolitis frequently required infliximab for steroid-refractory colitis.
Understanding of the upper gastrointestinal (GI) findings of ICI-related adverse events is limited. In a study conducted by Marthey et al., 24 of 22 patients who underwent upper GI endoscopy, nine manifested with gastritis, and two were diagnosed with erosive duodenitis. Furthermore, an analysis by Parente et al. 30 of the esophagogastroduodenoscopy results from eight patients identified the presence of gastric erythema and duodenal erosion, although the specific prevalence rates were not provided.
ICI-RELATED HISTOLOGIC FINDINGS
Histological findings in ICI-related diarrhea/colitis exhibit a characteristic overlap with histopathological characteristics associated with colitis prevalent in diverse entities, including IBD, ischemic colitis, infectious colitis, and microscopic colitis. 32 Most of the histologic findings displayed characteristics of acute inflammation, including cryptitis, crypt abscess, and infiltration of inflammatory cells in the epithelium and lamina propria. 15 , 23 , 24 , 26 , 29 - 31 , 33 , 34 Crypt irregularity/distortion, indicative of lesion chronicity, has been reported in 36% to 60% of instances. 15 , 23 , 28 , 31 , 33 Additionally, some studies identified intraepithelial lymphocyte infiltration, a manifestation of microscopic colitis. 15 , 31 , 33 Lastly, apoptosis was observed in a spectrum ranging from of 20% to 76% across various studies. 15 , 23 , 24 , 30 , 31 , 33 In a small case series comprising seven patients, every specimen demonstrated apoptotic features. 26
Several studies have classified histological findings. Wang et al. 15 classified them into chronic inflammation (60.4%), acute inflammation (22.6%), and lymphocytic colitis (7.5%). No significant differences in colitis treatment or symptom severity were observed between the histological groups. Parente et al. 30 categorized them into ischemic, apoptotic, and eosinophilic patterns. These patterns overlapped with each other, and this study did not analyze the prognostic differences according to distinct histological types. Cheung et al. 34 classified these ICI-related findings into several categories based on their similarity to pathological findings in other conditions and categorized them as nonsteroidal anti-inflammatory drugs (NSAIDs)/infectious-like (32%), IBD-like (28%), lymphocytic colitis (20%), focal acute colitis (11%), and collagenous colitis (9%). Subsequently, they presented a frequency distribution by allocating all cases to one of these distinct categories. The proportion of patients with steroid-refractory colitis was higher in the NSAID/infectious (46%) and IBD-like (53%) groups compared to those in the other groups. In addition, a positive correlation was observed between the histological activity assessed using the Nancy score and endoscopic severity assessed using the UC endoscopic index of severity. Table 4 summarizes the pathological findings in ICI-related colitis. Considering the information provided by such pathological findings, current clinical guidelines recommend performing a biopsy in patients suspected of having ICI-related colitis. 16 - 18
Table 4.
Immune checkpoint inhibitor-related histologic findings
ICI, immune checkpoint inhibitor; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; m/c, most common; PD-1, programmed cell death protein 1; PD-L1, programmed cell death-ligand 1; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; NSAID, nonsteroidal anti-inflammatory drug.
| Study | Year | No. of patients | Type of malignancy | Target of ICI | Histologic finding |
| Verschuren et al. 31 | 2016 | 25 | Prostate cancer, melanoma | CTLA-4 | Intraepithelial neutrophilic lymphocytes (72%), cryptitis (92%), crypt abscess (60%), crypt irregularities (40%), apoptosis (20%) |
| Marthey et al. 24 | 2016 | 27 | Melanoma (m/c), prostate cancer, lung cancer | CTLA-4 | Acute colitis feature (focal active colitis with patchy crypt abscesses or diffuse mucosal acute inflammation, 96.3%), mild eosinophilic infiltrates (70.4%), mild apoptosis (40.7%) |
| Gonzalez et al. 28 | 2017 | 17 | Melanoma, lung cancer | PD-1/PD-L1 | Crypt distortion (53%), lamina propria expansion (76%), intraepithelial neutrophil (71%) |
| Geukes Foppen et al. 23 | 2018 | 90 | Melanoma (87%), NSCLC (13%) | CTLA-4 (56%), PD-1 (23%), combination (21%) | Increased Lamina propria cellularity (83%), intraepithelial neutrophilic infiltration (79%), neutrophilic crypt abscesses (62%), apoptotic cells in crypt epithelium (42%), extension of chronic inflammatory infiltrate into submucosa (42%), irregular crypt architecture (36%), lymphocytosis (27%) |
| Wang et al. 15 | 2018 | 53 | Melanoma (70%) | CTLA-4 (69.8%), PD-1 (13.2%), CTLA-4+PD-1 (17.0%) | Chronic inflammation pattern (basal lymphocytic infiltrate, cryptic architecture distortion, and Paneth cell metaplasia, 60.4%), acute inflammation pattern (neutrophilic or eosinophilic infiltrate, cryptitis, crypt abscess, and apoptosis, 22.6%), intraepithelial infiltration of lymphocytes (7.5%), normal (9.4%), presence of apoptosis (22.6%) |
| Yanai et al. 26 | 2020 | 7 | Multiple myeloma, RCC, NSCLC | PD-1 | Acute inflammation (100%), cryptitis (100%), crypt abscess (100%), apoptosis (100%) |
| Cheung et al. 34 | 2020 | 45 | Metastatic melanoma, NSCLC, renal/urothelial cancer | CTLA-4, PD-1, combination (CTLA-4+PD-1) | NSAID/infectious-like colitis (32%), IBD-like colitis (28%), lymphocytic colitis (20%), focal acute colitis (11%), collagenous colitis (9%) |
| Parente et al. 30 | 2022 | 8 | Melanoma (m/c) | PD-1/PD-L1, CTLA-4, combination (PD-1+CTLA-4) | Ischemic pattern (necrotic mucosa, neutrophilic infiltrate with blood vessels ectasia), apoptotic pattern (glandular atrophy and distortion, apoptotic bodies in the glandular element), eosinophilic pattern (eosinophilic infiltrates in the lamina propria) |
| Bonanno et al. 33 | 2024 | 25 | NSCLC | PD-1/PD-L1 | Crypt atrophy/loss (48%), crypt distortion (60%), cryptitis (20%), crypt abscess (8%), mucin depletion (80%), apoptotic bodies (76%), collagenous band (36%), intraepithelial lymphocytes (96%), lymphocyte infiltrate (100%), granulocyte infiltrate (48%), ischemic colitis-like (24%) |
MANAGEMENT OF ICI-RELATED COLITIS
According to recently introduced comprehensive guidelines, corticosteroids should be considered a first-line treatment for ICI-related diarrhea/colitis of CTCAE grade 2 or higher. 16 , 18 Depending on the endoscopic severity, intravenous (IV) treatment can also be considered for moderate/severe cases. If histological evaluation indicates features of microscopic colitis, administration of budesonide or oral beclomethasone is recommended. Hughes et al. 35 documented the effectiveness of budesonide in relieving symptoms and prolonging immunotherapy in patients with ICI-related microscopic colitis. In a recent case report, oral beclomethasone was reported to induce clinical and histologic remission in two patients with ICI-related microscopic colitis. 36 Furthermore, Alexander et al. 37 reported that oral beclomethasone administration led to a clinical response in all 22 patients diagnosed with ICI-related colitis, with 50% of patients displaying no disease activity on endoscopic examination, while the remaining 50% were confirmed to have endoscopic colitis. In cases where corticosteroids result in suboptimal outcomes, escalation of the steroid dosage or a transition from oral to IV administration may be warranted. In steroid-refractory cases, the use of biological agents should be considered, with infliximab and vedolizumab being the currently recommended options. 16 , 38 , 39 A recent study by Zou et al. 40 reported that the efficacies of these two options are comparable. Therefore, the decision to use biologics should be approached selectively, considering the specific underlying medical conditions of the patient. The investigation of biological agents and small molecules in managing ICI-related microscopic colitis is also warranted, as emerging data suggest their effectiveness for refractory microscopic colitis originating from etiologies other than ICI use. 41 , 42 Figure 1 illustrates the management flow of ICI-related diarrhea/colitis.
CONCLUSIONS
ICI-related diarrhea and colitis account for a significant proportion of irAEs. For ICI-related diarrhea/colitis with symptoms of CTCAE grade 2 or higher, endoscopic evaluation becomes necessary. The distribution of ICI-related colitis demonstrates a high frequency of extensive colitis, followed by left-sided colitis. The endoscopic findings are diverse and often mimic those of IBD. The presence of ulcers and the widespread distribution of intestinal inflammation are associated with steroid refractoriness. Microscopic inflammation is often present in endoscopically normal mucosa, necessitating biopsies even for normal lesions. The histological findings vary, including acute and chronic inflammation, along with characteristics similar to those observed in IBD and microscopic colitis. Corticosteroids are recommended as first-line treatment for ICI-related diarrhea/colitis, whereas budesonide and oral beclomethasone are suitable for microscopic colitis. For steroid-refractory cases, infliximab and vedolizumab are recommended, with the choice of a biologic agent tailored to the specific patient. Moreover, ICI-related diarrhea/colitis manifests as a spectrum of clinical courses and, in severe cases, may necessitate the cessation of cancer immunotherapy. Any delay in cancer treatment can adversely affect the survival outcomes of the patient, underscoring the importance of prompt diagnosis and management of this disease. Therefore, a multidisciplinary team approach is essential for the diagnosis and management of ICI-related diarrhea/colitis.
Footnotes
Conflicts of Interest
The authors have no potential conflicts of interest.
Funding
This work was supported by a grant from the Korean Gastroenterology Fund for Future Development and a grant (2022IP0079, 2023IP0058) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.
Author Contributions
Conceptualization: SWH; Data curation: all authors; Formal analysis: all authors; Investigation: MKK; Methodology: SWH; Supervision: SWH; Wiring–original draft: all authors; Writing–review & editing: SWH.
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