This systematic review characterizes adverse drug reactions (ADRs) associated with cadonilimab (AK104), a bispecific immune checkpoint inhibitor, to inform clinical safety protocols. We conducted a comprehensive literature search across PubMed, Web of Science, and Chinese databases (CNKI, Wanfang Data, VIP Network), identifying 16 case studies involving 22 patients (11 male, 11 female; age range: 34–81 years). Geriatric patients (≥60 years) accounted for 68.2% (15/22) of ADR cases, with 36.4% (8/22) receiving concomitant pharmacotherapies. ADR onset exhibited temporal heterogeneity, ranging from 1 day to 9 months post-administration, with 72.7% (16/22) occurring within the first 90 days. Symptomatic intervention and therapy discontinuation resulted in clinical resolution in 90.9% (20/22) of cases, while longitudinal outcomes remained undocumented for 22.7% (5/22). Organ-specific toxicity profiles revealed predominant involvement of the integumentary (36.4%, 8/22), cardiovascular (31.8%, 7/22), and endocrine systems (18.2%, 4/22), consistent with immune-related adverse event patterns. These findings underscore the necessity for protocolized surveillance of cutaneous, hemodynamic, and metabolic parameters during early-phase treatment cycles (≤90 days post-initiation). This evidence base supports risk-benefit reassessment for next-generation immunotherapeutics and informs precision monitoring strategies to optimize therapeutic indices in oncologic applications.