Cancer immunotherapy under immune pressure: Mechanisms of resistance and the shift toward precision immune engineering.

Cancer immunotherapy has transformed the treatment landscape across multiple malignancies; however, durable responses remain limited to a subset of patients due to the emergence of intrinsic and acquired resistance. Increasing evidence suggests that therapeutic immune pressure itself acts as a selective force that shapes tumour evolution, driving the outgrowth of resistant clones. In this review, we synthesise current understanding of the molecular and cellular mechanisms underlying resistance to major immunotherapeutic modalities, including immune checkpoint inhibitors, adoptive cell therapies, and cancer vaccines. We discuss tumour-intrinsic alterations such as defects in antigen presentation and immune signalling pathways, alongside tumour-extrinsic factors including immunosuppressive cell populations, metabolic constraints, and microbiome-mediated modulation. We further examine how these mechanisms converge within the tumour microenvironment to limit therapeutic efficacy. Emerging strategies to overcome resistance are highlighted, including rational combination therapies, next-generation engineered cellular platforms, and precision-guided approaches enabled by multi-omics profiling and artificial intelligence. Collectively, we propose that resistance should be understood as an adaptive consequence of therapeutic immune pressure. Building upon the principles of cancer immunoediting, we discuss how precision immune engineering, the rational design of personalised immunotherapeutic strategies informed by tumour biology, immune context, and predictive biomarkers, may be used to anticipate and overcome evolutionary escape mechanisms.