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Cancer therapy is undergoing a paradigm shift driven by five distinct next-generation modalities. Despite advances in immune checkpoint inhibition and targeted therapy, a substantial proportion of patients with advanced malignancies fail to achieve durable responses [43,44]. This systematic review provides an integrated comparative analysis of antibody–drug conjugates (ADCs), bispecific antibodies (BsAbs), CAR-T cell therapy, mRNA cancer vaccines, and radioligand therapy (RLT), with attention to their histotype-specific versus pan-tumour applicability. A PRISMA 2020-compliant systematic search of PubMed/MEDLINE, Scopus, CENTRAL, and ClinicalTrials.gov was conducted covering January 2018 through May 2025 [45]. Phase 2–3 randomised controlled trials, pivotal single-arm trials, and regulatory submissions were eligible. Risk of bias was assessed using RoB 2.0 and ROBINS-I. 128 eligible studies were identified. ADCs – led by trastuzumab deruxtecan (T-DXd) – established the first tumour-agnostic ADC approval in 2024, with mPFS of 28.8 vs 6.8 months over T-DM1 in HER2+ breast cancer (HR 0.33) [2]. BsAbs yielded ORRs of 40–80% across haematological and solid tumour indications [13–20]. The first randomised CAR-T trial in a solid tumour (satri-cel vs TPC in gastric cancer) demonstrated significant PFS improvement in 2025 [26]. mRNA-4157 plus pembrolizumab reduced melanoma recurrence risk by 44% (HR 0.56) [31]. [¹⁷⁷Lu]Lu-PSMA-617 extended OS by 4 months over standard care in mCRPC (HR 0.62) [39]. All five modalities have achieved regulatory approvals and clinically meaningful efficacy. Combinatorial strategies, predictive biomarker development, and equitable access are the foremost challenges for the field.