Reprogramming cancer immunity with next-generation combination therapies

Abstract

Cancer immunotherapy has fundamentally reshaped oncology by harnessing the immune system to eliminate malignant cells. Immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1 have achieved durable remissions in select cancers, yet most patients exhibit resistance due to tumor heterogeneity, immunometabolic rewiring, and the immunosuppressive tumor microenvironment. To address these limitations, next-generation immunotherapies have emerged, targeting multiple layers of immune regulation. These include co-inhibitory and co-stimulatory checkpoint modulators, bispecific antibodies, adoptive cell therapies, cancer vaccines, oncolytic viruses, cytokine-based strategies, and synthetic immunomodulators that activate innate sensors. Nanotechnology and in vivo immune engineering further enhance specificity, reduce toxicity, and broaden applicability. Combination immunotherapy has become central to overcoming resistance, with rational regimens integrating ICIs, cytokines, vaccines, and targeted agents. Biomarker-guided strategies, leveraging tumor mutational burden, immune cell infiltration, and multi-omic profiling, are enabling personalized approaches. However, immune-related adverse events and variability in therapeutic responses necessitate predictive biomarkers and improved patient stratification. Emerging frontiers include microbiome-targeted interventions, chronotherapy, and AI-driven modeling of tumor-immune dynamics. Equally critical is ensuring global equity through inclusive trial design, diverse biomarker validation, and expanded access to cutting-edge therapies. This review provides a comprehensive analysis of multimodal immunotherapeutic strategies, their mechanistic basis, and clinical integration. By unifying innovation in immunology, synthetic biology, and systems medicine, next-generation cancer immunotherapy is poised to transition from a transformative intervention to a curative paradigm across malignancies.

Keywords: adoptive cell therapy; biomarker-guided precision medicine; cancer immunotherapy; immune checkpoints; next-generation therapeutics; tumor microenvironment.

FIGURE 1

Landscape of cancer immunotherapies. (A) Therapeutic cancer vaccines stimulate endogenous T cell immune responses against tumor antigens. This process begins with the uptake, processing, and presentation of antigens by dendritic cells. Immune activation can be induced through various methods, including the injection of naked or nanoparticle-encapsulated DNA, RNA, or peptides, ex vivo pulsing of autologous dendritic cells, and the administration of irradiated tumor cells. Antigen presentation is mediated by specific human leukocyte antigens (HLA) within the major histocompatibility complex (MHC) I and II, which activate CD8⁺ and CD4⁺ T cells, respectively. (B) BiTEs have emerged as a key class of immunotherapeutic agents in oncology. These recombinant proteins consist of two antigen-binding modules connected by a short linker sequence or a shared Fc domain. One module binds to a tumor-associated antigen (TAA), while the other engages a T cell activation molecule, such as CD3 on the T cell receptor (TCR) complex. The simultaneous binding of BiTEs to both the tumor antigen and the TCR leads to T cell activation, the formation of immune synapses, and tumor cell lysis. BiTEs can be engineered to target various TAAs, offering broad therapeutic potential across multiple cancer types. (C) Adoptive cell therapies involve the ex vivo expansion and infusion of autologous or allogeneic immune cells to enhance tumor eradication. The most widely used adoptive cell therapies include tumor-infiltrating lymphocytes (TILs) and genetically modified T cells expressing transgenic TCRs or chimeric antigen receptors (CARs). Unlike TILs and transgenic TCR T cells, CAR-T cells function independently of MHC molecules and can be designed to target a wide range of TAAs. Additionally, gene modification strategies have been developed to enhance adoptive cell therapies efficacy in solid tumors. These include engineering natural killer (NK) cells and macrophages to express transgenic TCRs, NK cell receptors, CARs, or TCR-like CARs. (D) Oncolytic viruses represent a dual-action cancer therapy that combines direct cancer cell lysis with immune system activation. Upon infection, cancer cells initiate an antiviral response involving endoplasmic reticulum and genotoxic stress, leading to increased reactive oxygen species (ROS) and the production of antiviral cytokines, particularly type I interferons (IFNs). These signals activate immune cells, including antigen-presenting cells, CD8⁺ T cells, and NK cells. Oncolysis releases viral progeny, pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and TAAs, including neoantigens. The released viral progeny propagates the infection, while PAMPs and DAMPs stimulate immune receptors such as Toll-like receptors (TLRs). This immune-stimulatory environment enhances antigen presentation and promotes the generation of immune responses against both virally infected and uninfected cancer cells expressing TAAs and neoantigens.