Immunotherapy in cancer: Mechanisms and strategies to overcome resistance

Recent advances in the field of oncology have increased our understanding of the immune system, its response to malignancies and the immune component of the tumor microenvironment (TME). Indeed, information obtained about tumor biology has become an important strategy in developing treatments for cancer. A plethora of immunotherapy drugs have been approved and have been shown to be efficacious in treating cancers resistant to other therapeutic modalities. However, these drugs produce autoimmunity and non-specific inflammation, and therapeutic resistance can occur. Resistance to immunotherapeutic drugs can be due to: (i) tumor-intrinsic antigens or histocompatibility leukocyte antigens (HLA) loss; (ii) adaptive signaling changes (e.g., phosphoinositide-3-kinase (PI3K)/AKT, mitogen-activated protein kinase (MAPK), Janus kinase (JAK)/signal transducers and activator of transcription (STAT)) and (iii) immunosuppressive TME. Antibody drug conjugate (ADC)-specific issues include target density thresholds, impaired internalization, lysosomal trafficking defects and payload efflux, which could be overcome by rational drug combinations (i.e., immune checkpoint inhibitors (ICI) and virtual reality (VR) blockade, ADC and programmed cell death protein 1 (PD-1) inhibitors, chimeric antigen receptor (CAR) - T cells and interleukin-12 (IL-12)), TME reprogramming (e.g., tumor growth factor-beta (TGFβ) or stimulator of interferon genes (STING) modulators and next-generation constructs (e.g., bispecific antibodies, immune-stimulating ADCs, proteolysis targeting chimera (PROTAC) conjugates). In this review, we provide a cross-platform analysis, with a significant emphasis on ADCs, which has a dual chemical-biological nature that epitomizes the complexity of contemporary drug design.