Gastric cancer, a leading cause of cancer-related deaths worldwide, presents a significant therapeutic challenge. Current standard treatments, including first-line chemotherapy regimens (fluoropyrimidine and platinum-based, with trastuzumab for HER2-overexpressing cancers) and second-line therapies (paclitaxel with or without ramucirumab), offer limited improvements in overall survival (OS), typically resulting in a median survival of only 12–15 months for advanced gastric cancer (AGC). The development and approval of immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, providing a new avenue for improving outcomes in several cancer types. This review focuses on the latest advancements in immunotherapy and molecular targeted therapies for gastric cancer, highlighting the role of ICIs as a cornerstone of treatment development and exploring promising combination strategies that could significantly enhance patient survival and quality of life. The increasing understanding of the molecular and genomic characteristics of gastric cancer is crucial to tailoring treatments to individual patient needs and maximizing therapeutic benefits.

The 2014 Cancer Genome Atlas (TCGA) study identified four molecular subtypes of gastric cancer: Epstein-Barr virus (EBV)-positive, microsatellite instability-high (MSI-H), chromosomal instability (CIN), and genomically stable (GS). These subtypes exhibit distinct molecular profiles and immunological signatures influencing their responsiveness to different therapies. Studies have shown that EBV-positive and MSI-H gastric cancers often demonstrate higher response rates to ICIs due to their distinct immunologic characteristics. Conversely, CIN tumors frequently exhibit mechanisms that suppress immune infiltration, presenting a challenge for ICI therapy. The expression of PD-L1, a key immune checkpoint molecule, is also crucial for determining ICI efficacy, leading to the use of the combined positive score (CPS) as a predictive biomarker.

This review synthesizes current evidence from clinical trials and preclinical studies focusing on immunotherapy and molecular targeted therapies in gastric cancer. The authors analyze data from pivotal phase II and III trials evaluating different ICIs (anti-PD-1, anti-PD-L1, anti-CTLA-4), their combinations with chemotherapy and targeted agents, as well as emerging approaches like bispecific antibodies and CAR-T cell therapy. The review examines the efficacy, safety, and predictive biomarkers associated with these treatments across various treatment lines (first-line, second-line, third-line and later) and settings (perioperative). The discussion encompasses the impact of molecular subtypes (EBV+, MSI-H, CIN, GS) and tumor mutation burden (TMB) on treatment response. The authors critically assess the results of trials investigating different combination strategies including ICIs with multikinase inhibitors (e.g., regorafenib, lenvatinib), HER2-targeted therapies (e.g., trastuzumab, trastuzumab deruxtecan, margetuximab, zanidatamab, tucatinib), and CLDN18.2-targeted agents (e.g., zolbetuximab). Additionally, the review explores ongoing research involving other immune checkpoints (LAG-3, TIGIT) and advanced cell therapies (CAR-T cells).

Several key findings emerge from the review: **First-line Setting:** * KEYNOTE-062: Pembrolizumab monotherapy showed non-inferiority to chemotherapy in patients with CPS ≥1, while a trend towards improved OS was observed with CPS ≥10. * CheckMate-649: Nivolumab plus chemotherapy significantly improved OS and PFS, irrespective of PD-L1 expression. * KEYNOTE-859: Pembrolizumab plus chemotherapy demonstrated improved OS and PFS compared to chemotherapy alone in HER2-negative AGC. * RATIONALE-305: Tislelizumab plus chemotherapy showed a significant OS benefit compared to chemotherapy alone in PD-L1-positive patients. * ORIENT-16: Sintilimab plus chemotherapy showed superiority to chemotherapy alone in terms of OS in all patients, and even more prominently in patients with CPS ≥5. **Second-line Setting:** * KEYNOTE-061: Pembrolizumab did not demonstrate a significant OS advantage over paclitaxel for patients with CPS ≥1; however, subgroups (ECOG PS 0, CPS ≥10, MSI-H) showed benefit. **Third- and Later-line Setting:** * ATTRACTION-2: Nivolumab significantly improved OS and PFS compared to placebo in patients refractory to at least two prior chemotherapy regimens. * KEYNOTE-059: Pembrolizumab demonstrated efficacy and safety in the third-line or later-line settings. * JAVELIN 300: Avelumab failed to show an OS benefit compared to investigator-chosen chemotherapy. **Perioperative Setting:** * NEONIPIGA: Neoadjuvant nivolumab plus ipilimumab showed a high pathological complete response (pCR) rate in localized MMR-D/MSI-H cancers. **Combination Therapies:** * Combination of anti-PD-1 with anti-CTLA-4 antibodies: CheckMate-649 showed varying efficacy depending on PD-L1 expression, highlighting the need for better understanding patient selection criteria. * Combination of anti-PD-1 with multikinase inhibitors (regorafenib, lenvatinib): Preclinical and clinical data suggest synergistic antitumor activity. * Combination of anti-PD-1 with HER2-targeted therapies: KEYNOTE-811 demonstrated a significant improvement in ORR with pembrolizumab plus trastuzumab and chemotherapy for HER2-positive AGC. Other trials showed the same positive outcome with different treatment strategies. * Combination of anti-PD-1 with CLDN18.2-targeted therapies: Zolbetuximab plus chemotherapy improved survival in CLDN18.2-positive AGC patients. **Other Immune Checkpoints:** Trials targeting LAG-3 and TIGIT, along with bispecific antibodies (BsAbs) and CAR-T cell therapies, are ongoing and show potential benefits.

The findings of this review underscore the remarkable progress in immunotherapy and targeted therapies for gastric cancer. The efficacy of ICIs, particularly anti-PD-1/PD-L1 antibodies, has been established in several clinical trials, especially when combined with chemotherapy. However, the substantial variation in response rates highlights the need for accurate biomarker identification to improve patient selection. While PD-L1 expression and CPS have been used, further research is warranted to refine predictive biomarkers for ICI treatment. The exploration of combination therapies – including the use of multikinase inhibitors, targeted agents, and other immune checkpoint inhibitors – offers great promise in enhancing antitumor activity and overcoming resistance. The success of combining anti-PD-1 agents with HER2-targeted therapies for HER2-positive gastric cancer exemplifies this trend. The development of novel immunotherapies, such as those targeting LAG-3 and TIGIT, and the advancement of cell-based therapies like CAR-T cells, further broaden the therapeutic landscape. These approaches hold the potential to offer long-term survival benefits and improved quality of life for gastric cancer patients.

Significant progress has been made in immunotherapy and molecular targeted therapy for gastric cancer. ICIs, especially anti-PD-1/PD-L1 antibodies, have emerged as a mainstay of treatment, particularly in combination with chemotherapy. However, response rates vary significantly, highlighting the need for better predictive biomarkers to guide treatment decisions. The development of combination strategies, involving other ICIs, targeted agents, and advanced cell therapies, offers considerable potential for enhanced efficacy and improved outcomes. Future research should focus on identifying robust biomarkers, exploring novel therapeutic targets, and optimizing combination regimens to improve patient selection and maximize the therapeutic benefit of these promising treatments.

This review is limited to the published literature available at the time of writing and may not include very recently published information. The interpretation of some findings is affected by the heterogeneity of study populations, treatment regimens, and evaluation methods across different clinical trials. The long-term effects and potential long-term side effects of some of these newer combination treatments may not be fully known yet. The results of several ongoing clinical trials are yet to be reported and may significantly alter the current understanding of optimal treatments.