Advancing human epidermal growth factor receptor 2-positive gastric cancer therapy: Toward targeted immunotherapy and antibody-drug conjugates

Table 3 Overview of novel therapeutic modalities for human epidermal growth factor receptor 2-positive gastric cancer

Therapeutic category	Regimen/agents	Mechanism of action	Current limitations/challenges	Ref.
Bispecific antibodies	PRS-343	Targets HER2 and 4-1BB, promoting T-cell proliferation and cytokine production via HER2-dependent 4-1BB clustering	Preclinical stage; clinical validation needed for potential risks like CRS	Hinner et al[78]
	IBI315	Concurrently blocks PD-1 and HER2 signaling, establishing a self-reinforcing immunostimulatory cycle via gasdermin B-mediated pyroptosis	Efficacy and safety need confirmation in large-scale clinical trials	Lin et al[79]
	KN026	Recognizes two distinct HER2 domains, achieving potent dual HER2 signal blockade	Optimal combination regimens and long-term benefits need exploration, despite promising ORR (56%)	Ji et al[80]
	CD40 × HER2	Activates CD40 signaling to repolarize macrophages towards the M1 antitumor phenotype, reversing C-C motif chemokine ligand-driven resistance	Preclinical stage; long-term in vivo safety and efficacy require evaluation	Sun et al[82]
	IMM2902	Targets CD47 and HER2, stimulates macrophages to recruit T and NK cells via CXCL9/CXCL10	Clinical potential awaits validation in human trials	Zhang et al[83]
CAR-T cell therapy	HER2 CAR-T	Genetically engineered T cells express HER2-specific CARs for targeted tumor cell elimination	Immunosuppressive TME; risk of on-target/off-tumor toxicity; cytokine release syndrome and neurotoxicity; antigen heterogeneity	Budi et al[85]; Xu et al[86]; Qi et al[88]; Simon et al[89]; Guzman et al[90]
	ARC-T cells	Achieves selective tumor cell killing while minimizing off-tissue toxicity through spar X affinity and dose modulation	Early development stage; clinical translation potential needs validation	Mu et al[91]
Targeted thorium conjugates	HER2-TTC	Delivers the alpha-particle emitter thorium-227 to HER2+ cells, inducing potent, localized DNA double-strand breaks	Efficacy depends on sustained HER2 expression; limited clinical data (trial No. NCT04147819 ongoing); long-term safety requires evaluation	Pernas et al[35]; Wickstroem et al[92]; Karlsson[93]; Garg et al[94]; Anderson et al[95]

CAR-T: Chimeric antigen receptor T-cell immunotherapy; HER2: Human epidermal growth factor receptor 2; CD: Cluster of differentiation; ARC: Acrobatic recombinase cassette; TTC: Targeted thorium conjugate; CCL: C-C motif chemokine ligand; PD-1: Programmed cell death 1; NK: Natural killer; CRS: Cytokine release syndrome; ORR: Objective response rate; TME: Tumor microenvironment.