For patients with initially unresectable advanced gastric cancer (GC), systemic therapy remains the cornerstone of treatment. Immune checkpoint inhibitors (ICIs) have improved outcomes in selected advanced-disease populations. CheckMate 649 trial demonstrated a survival benefit from nivolumab plus chemotherapy in human epidermal growth factor receptor 2 (HER2)-negative disease, particularly at higher programmed death-ligand 1 (PD-L1) combined positive scores (CPS) [1]. Other first-line studies have evaluated similar chemotherapy–immunotherapy combinations [2, 3].

Cadonilimab is a bispecific antibody targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). In the COMPASSION-15 trial, cadonilimab plus chemotherapy improved outcomes in HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma [4]. These trial findings do not directly establish its role in a HER2-positive conversion regimen.

Conversion surgery should be considered when initial unresectable disease becomes amenable to complete macroscopic response after induction systemic therapy [5]. Retrospective studies have described ICI-containing conversion strategies, although the treated populations and regimens differ [6, 7].

In this report, we present a 51-year-old man with clinical stage IV GC and multiple liver lesions who received systemic oxaliplatin plus S-1 (SOX), cadonilimab, and disitamab vedotin before conversion surgery. No viable tumor was identified in the gastric resection specimen or sampled lymph nodes.

The focused narrative review addresses ICI-containing systemic therapy followed by conversion surgery in initially unresectable GC.

A 51-year-old Chinese man presented in December 2025 with a 1-month history of epigastric fullness and discomfort. He had no significant past medical history, no family history of GC, and no history of smoking or alcohol abuse.

Esophagogastroduodenoscopy (EGD) revealed an ulcerative-infiltrative lesion involving the gastric angle and antrum, classified as Borrmann type III (advanced GC). Abdominal contrast-enhanced computed tomography (CT) revealed circumferential wall thickening of the gastric antrum, as well as multiple hypodense nodular lesions in the liver (two lesions, maximum diameter 2 cm) consistent with metastatic disease (Fig. 1).

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Figure 1. Contrast-enhanced computed tomography (CT) images before and after systemic therapy. (a) Baseline (December 2025) CT showing gastric wall thickening and multiple hypodense liver lesions. (b) Restaging CT (March 2026) showing that the liver lesion is less distinct than before, suggesting that the lesion may be resolving. (c) Restaging CT (October 2026) showing no evidence of hepatic recurrence or new metastatic lesions.

Histological examination of the biopsy showed moderately to poorly differentiated adenocarcinoma. Immunohistochemistry (IHC) showed HER2 3+ (Fig. 2a–d) and positive expression of mutL homolog 1 (MLH1), postmeiotic segregation increased 2 (PMS2), mutS homolog 2 (MSH2), and mutS homolog 6 (MSH6), consistent with proficient mismatch repair (pMMR) (Fig. 3a–d). The PD-L1 (22C3) CPS was 30, and the Ki-67 index was approximately 90%. Both neuroendocrine markers and Epstein–Barr virus-encoded small RNAs were negative.

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Figure 2. Pre-treatment endoscopic biopsy of gastric carcinoma. (a) Hematoxylin and eosin (H&E) staining, × 10 magnification, poorly differentiated adenocarcinoma. (b) Human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC), × 10, 3+ complete membranous staining. (c) Ki-67 proliferation index IHC, × 10, 90%. (d) Programmed death-ligand 1(22C3) IHC, × 10, combined positive score (CPS) = 30.

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Figure 3. Mismatch-repair protein immunohistochemistry of pre-treatment biopsy specimen (× 10). (a) mutL homolog 1 (MLH1) positive; (b) mutS homolog 2 (MSH2) positive; (c) mutS homolog 6 (MSH6) positive; (d) postmeiotic segregation increased 2 (PMS2) positive, consistent with proficient mismatch-repair (pMMR) status.

The patient was clinical staged as cT3NxM1, stage IV (gastric adenocarcinoma with synchronous liver metastases).

Because the patient was initially unsuitable for curative surgery (multiple liver metastases and para-aortic node metastases), systemic treatment was initiated, comprising oxaliplatin 200 mg/m² by intravenous infusion (day 1), oral S-1 (tegafur/gimeracil/oteracil) 60 mg twice daily (days 1–14), and cadonilimab 375 mg and disitamab vedotin 120 mg by intravenous infusion. Treatment was repeated every 4 weeks for three cycles.

No significant adverse reactions, bone marrow suppression, or liver-function abnormalities were documented during treatment. Hepatoprotective agents, including polyene phosphatidylcholine and magnesium isoglycyrrhizinate, and antiemetics were administered as needed.

Approximately 5 weeks after three cycles (March 2026), restaging CT showed marked reduction in gastric wall thickening, smaller perigastric, hepatoduodenal, and para-aortic lymph nodes, and near-resolution of the previously visible liver lesions (Fig. 1b). No new lesions were identified.

Carcinoembryonic antigen levels dropped from 7.30 to 3.91 ng/mL. Because the liver lesions had markedly regressed and no new disease was visible, the multidisciplinary tumor board (MDT) considered complete macroscopic resection of the gastric disease feasible and recommended conversion surgery.

On April 13, 2026, the patient underwent distal gastrectomy with Billroth II reconstruction and D2 lymphadenectomy (perigastric, celiac, hepatic, splenic, and para-aortic nodal stations), jejunojejunostomy (Braun anastomosis), and abdominal drainage tube placement.

Intraoperative findings included a firm mass at the gastric antrum (approximately 3 × 3 × 2 cm, not penetrating the serosa), enlarged perigastric lymph nodes with fibrotic changes, and a grossly normal liver with no palpable suspicious lesions.

The liver was mobilized and examined using intraoperative ultrasound. Mild steatosis was noted, and no metastatic lesions were detected. No liver lesions were biopsied or resected.

The patient experienced a smooth and rapid postoperative recovery, with no intraoperative or postoperative complications.

The most recent follow-up imaging (contrast-enhanced CT of the abdomen in October 2026) showed no evidence of lesion progression or new lesions, indirectly supporting our clinical judgment of an R0 resection and complete response.

Gross examination of the gastrectomy specimen revealed a vaguely defined fibrotic area in the antrum corresponding to the previous tumor site, and the entire tumor bed was submitted for histological evaluation.

Microscopic analysis revealed no viable tumor cells, while the presence of fibrosis, inflammation, foamy histiocytes, and multinucleated giant cells were consistent with treatment effect (tumor regression grade (TRG) 0). All 33 examined lymph nodes were negative (0/33), including three with treatment-associated changes (Fig. 4a–f). Gastric resection margins were negative, and the pathological staging was determined to be ypT0N0.

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Figure 4. Post-treatment surgical resection specimen showing complete pathological regression in the examined gastric and nodal tissue (tumor regression grade 0). (a, b) Primary tumor bed with extensive stromal fibrosis and inflammatory cell infiltration, no viable tumor cells identified (hematoxylin and eosin (H&E) staining; original magnification, × 10 (a) and × 20 (b)). (c, d) Foamy histiocytes and stromal fibrosis (H&E staining; original magnification, × 10 (c) and × 20 (d)). (e, f) Lymph node showing post-treatment reactive changes without metastatic carcinoma (H&E staining; original magnification, × 10 (e) and × 20 (f)).

This narrative review focuses on original reports of ICI-containing systemic treatment followed by conversion surgery in initially unresectable GC. Planned preoperative treatment of initially resectable disease, chemotherapy-alone cohorts, case reports, and meta-analyses were not combined in a single response-rate denominator.

A previous study [6] reported the outcomes of ICI-based conversion therapy in 73 patients with initially unresectable GC (75.3% stage cIV). The pathological complete response (pCR) and major pathological response (MPR) rates were 24.7% and 37.0%, respectively, with the complete (R0) resection rate of 82.2%. The median overall survival was 41.3 months in the entire cohort. Nishi et al [7] reported conversion surgery in 11 of 36 initially unresectable metastatic patients after systemic treatment; 34 of the 36 received ICI plus chemotherapy.

Cadonilimab simultaneously targets PD-1 and CTLA-4 [8]. A separately published single-arm meta-analysis of cadonilimab-containing regimens reported a pooled pCR estimate of 23% across varied treatment settings [9].

This patient received SOX chemotherapy, cadonilimab, and disitamab vedotin concurrently. The HER2 3+ biopsy supported the use of the HER2-directed antibody-drug conjugate disitamab vedotin. SOX also had cytotoxic activity; the high Ki-67 index indicated high proliferation activity, which may have heightened chemotherapy sensitivity. Cadonilimab provided dual immune checkpoint blockade. The KEYNOTE-811 trial studied a different HER2-directed agent and checkpoint-inhibitor combination in advanced HER2-positive cancer [10], it cannot quantify the contribution of any drug in this case. Because all components were administered together, their individual effects and possible interactions cannot be separated.

Mismatch repair deficiency and PD-L1 expression have been associated with response to immune checkpoint blockade in advanced GC [11, 12], but findings across advanced-disease and preoperative settings should not be treated as validated predictors of pCR after conversion treatment. This patient had pMMR, a PD-L1 CPS of 30, and negative Epstein–Barr virus testing. These findings neither prove nor exclude a response to the combined regimen.

HER2-directed treatment plus chemotherapy has previously enabled conversion surgery. Hayano et al [13] reported surgery in six of 11 patients treated with trastuzumab-based chemotherapy, with R0 resection in four. In a multicenter retrospective cohort, Liang et al [14] reported conversion surgery in 50 of 118 patients receiving trastuzumab-based chemotherapy plus immunotherapy. Those approaches differ from the present combination of a HER2-directed antibody-drug conjugate, dual PD-1/CTLA-4 blockade, and SOX. The gastric, nodal pCR and resorption of metastatic lesions in this case add a pathological observation supporting further investigation of this combination as a conversion strategy.

The combination raises the hypothesis that targeting HER2 while blocking both PD-1 and CTLA-4 could deepen responses and increase opportunities for surgery compared with HER2-directed chemotherapy or conventional ICI-containing chemotherapy. However, this example is merely a case report, and this hypothesis still requires further large-scale prospective studies to be confirmed.

In a phase II study of disitamab vedotin in previously treated advanced GC, adverse events included cytopenias, fatigue, and elevated aminotransferases [15]. These toxicities may overlap with those of SOX; immune-mediated adverse events are an additional concern with checkpoint blockade [4]. Blood counts, liver function, and immune-related symptoms therefore require careful assessment during treatment and before surgery. The patient did not experience any significant adverse reactions, which is an encouraging result; however, the safety of this combination therapy still requires further validation.

These findings also raise questions about the additional benefit of gastrectomy after a deep response to systemic treatment. Although a firm gastric mass remained at surgery, the resected tumor bed contained no viable carcinoma. Thus, a pCR was established retrospectively through examination of the surgical specimen, rather than known when surgery was selected. This discrepancy highlights the difficulty of identifying patients who may already have achieved pathological clearance. Conversely, regression on imaging does not provide pathological confirmation at unsampled metastatic sites. The present case cannot determine whether surgery improved survival or could safely have been omitted. Future studies should assess residual disease, durability of response, operative risk, and outcomes with continued systemic therapy versus conversion surgery.

Several limitations should be acknowledged: (1) it is a single case report with limited generalizability; (2) the follow-up duration is relatively short; (3) it is difficult to distinguish the effects of SOX, cadonilimab, and disitamab vedotin (moreover, while complete pathological response was confirmed in the sampled gastric and nodal tissue, the regressed liver lesions on imaging were not sampled); and (4) no tissue-based immune profiling was performed.

This case report demonstrates that for some patients with initially unresectable HER2-positive GC, an intensive systemic treatment regimen combining HER2-targeted therapy, dual PD-1/CTLA-4 immune checkpoint inhibition, and chemotherapy may create an opportunity for conversion gastrectomy. However, the complete pathological remission achieved by this patient postoperatively also raises questions regarding whether surgery can still provide additional benefits for such patients after they have achieved a deep remission with systemic therapy. Therefore, extensive prospective studies are still needed to explore the relationship among tumor response, treatment toxicity, and surgical benefits in this patient population.

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