Advances in cancer immunotherapy: historical perspectives, current developments, and future directions

Abstract

Cancer immunotherapy, encompassing both experimental and standard-of-care therapies, has emerged as a promising approach to harnessing the immune system for tumor suppression. Experimental strategies, including novel immunotherapies and preclinical models, are actively being explored, while established treatments, such as immune checkpoint inhibitors (ICIs), are widely implemented in clinical settings. This comprehensive review examines the historical evolution, underlying mechanisms, and diverse strategies of cancer immunotherapy, highlighting both its clinical applications and ongoing preclinical advancements. The review delves into the essential components of anticancer immunity, including dendritic cell activation, T cell priming, and immune surveillance, while addressing the challenges posed by immune evasion mechanisms. Key immunotherapeutic strategies, such as cancer vaccines, oncolytic viruses, adoptive cell transfer, and ICIs, are discussed in detail. Additionally, the role of nanotechnology, cytokines, chemokines, and adjuvants in enhancing the precision and efficacy of immunotherapies were explored. Combination therapies, particularly those integrating immunotherapy with radiotherapy or chemotherapy, exhibit synergistic potential but necessitate careful management to reduce side effects. Emerging factors influencing immunotherapy outcomes, including tumor heterogeneity, gut microbiota composition, and genomic and epigenetic modifications, are also examined. Furthermore, the molecular mechanisms underlying immune evasion and therapeutic resistance are analyzed, with a focus on the contributions of noncoding RNAs and epigenetic alterations, along with innovative intervention strategies. This review emphasizes recent preclinical and clinical advancements, with particular attention to biomarker-driven approaches aimed at optimizing patient prognosis. Challenges such as immunotherapy-related toxicity, limited efficacy in solid tumors, and production constraints are highlighted as critical areas for future research. Advancements in personalized therapies and novel delivery systems are proposed as avenues to enhance treatment effectiveness and accessibility. By incorporating insights from multiple disciplines, this review aims to deepen the understanding and application of cancer immunotherapy, ultimately fostering more effective and widely accessible therapeutic solutions.

Keywords: Biomarker; Cancer immunotherapy; Clinical and pre-clinical; Immune evasion; Tumor microenvironment remodeling.

Fig. 1

The progress and use of cancer immunotherapy [44, 45]. Coley’s creation of vaccines established the groundwork for cancer immunotherapy. Since that time, notable progress has occurred, featuring the application of BCG as an adjuvant in immunotherapy and the emergence of monoclonal antibodies. Subsequently, cancer immunotherapy strategies integrated IFN-α, IL- 2, and tumor antigens. Since the 2000 s, significant attention has been directed toward the creation of drugs for cancer immunotherapy. The majority of these medications have received approval since 2010 and are currently utilized for treating both hematological and solid tumors. Alongside drug development, there has been a growing focus on the use of CAR-T cells in cancer immunotherapy. (Created with Biorender.com)

Fig. 2

A depiction showing the development of mature DCs via internal and external signals, their movement to lymph nodes, activation of T cells through targeted interactions, and the resulting inhibition of tumor cells. Cancer immunotherapy boosts immunosurveillance by activating DCs to obtain TAAs from tumors or vaccines. TAAs start the process of antigen processing and showcasing to naïve T cells in LNs via external cues, including TLR ligands or antibodies aimed at CD40, or internal signals from dying tumor cells. Based on TME and cytokines, DCs display TAAs on MHC molecules to T cells in LNs, which activates them and promotes their differentiation into CTLs or Tregs. Activated T cells experience clonal expansion and move toward tumor locations, directed by chemokines such as CXCL- 9 and CXCL- 10, along with adhesion molecules such as ICAM- 1. CTLs identify tumor cells via MHC-I molecules that display TAAs and release cytotoxic granules with perforin and granzymes to trigger the death of tumor cells. Moreover, cytokines such as IFN-γ and Fas-FasL interactions enhance the anti-tumor responses even more. The obliteration of tumor cells releases novel antigens, which boost immune responses and draw in more immune cells, thereby maintaining the therapeutic effect. (Created with Biorender.com)

Fig. 3

A diagram illustrating the progression of immune resistance and the potential therapeutic targets. A This illustration is centered on PD-L1, but it also pertains to various types of immune checkpoint inhibitors, such as PD-L2, which is referred to as B7-DC. In several cancers, the activation of oncogenic pathways can elevate PD-L1 levels in a manner that is not dependent on inflammatory signals in the TME. Additionally, it has been demonstrated that the overexpression of AKT and STAT3 leads to elevated levels of PD-L1. Nonetheless, there is an absence of PD-L1 expression in various cancer types, and its expression may arise due to inflammatory factors produced by the active immune responses against cancer. The varied expression of PD-L1 seen in different tumor regions with TIL infiltration indicates that PD-L1 expression arises from immune responses in the TME [115]. B The process of anti-cancer immunity includes multiple checkpoints [116]. Various types of co-receptors exist on cell surfaces that can either activate or inhibit immune responses. The majority of these receptors rely on TCR activity to recognize antigens presented by MHC molecules on APCs, delivering either inhibitory or stimulatory signals. These interactions have been noted in the peripheral regions or in secondary lymphoid tissues. Several receptors have specific motifs such as UVKM for CTLA- 4 and KIEELE for LAG3, while other inhibitory receptors exhibit ITIMs and/or ITSMs within their intracellular domains. Utilizing antibodies for checkpoint treatments to modify T cell inhibitory signals such as PD- 1 and CTLA- 4 can stimulate prolonged immune responses in individuals. Additional measures can be taken to enhance the effectiveness of immunotherapy in patients. One approach involves the use of PD- 1 and CTLA- 4 blockade alongside various antagonists of inhibitory receptors on T cells, such as TIM- 3, LAG- 3, TIGIT, and BTLA. Another approach is to combine ICB with the agonist of co-stimulatory receptors on T cells, such as CD27, 4 - 1BB, OX40, and GITR. The ultimate approach may involve using ICBs while promoting tumor antigen recognition through vaccines and activating dendritic cells with CD40 agonists. (Created by Biorender.com)

Fig. 4

The modulation of the immune system through chemotherapeutic agents. Various types of anti-cancer agents can target immune cells, potentially generating a synergistic effect in cancer immunotherapy. The presence of calreticulin along with the release of HMGB1 and ATP may lead to immunogenic cell death that facilitates DC activation by influencing NLRP3 and TLR4. Several chemotherapy medications can directly stimulate DCs. The heightened cross-presentation may result from gemcitabine, and several of them can inhibit or eliminate the immunosuppressive cells [209]. (Created by Biorender.com)

Fig. 5

The reasoning behind integrating radiotherapy and immunotherapy for cancer eradication [226]. It is important to recognize that radiotherapy has a dual role, making it essential to implement new strategies that harness the synergistic effects of radiotherapy. A Radiotherapy might have an immunostimulatory effect by enhancing the levels of neoantigen-encoding genes, boosting immunogenic cell death, and facilitating neoantigen presentation on MHC class I molecules. B Radiotherapy might also exert an immunosuppressive effect depending on the radiation dosage, fractionation schedule, and treatment area. The hypoxia might enhance TME remodeling to encourage the M2 polarization of macrophages while promoting the infiltration of Treg cells and activating CAFs. Conversely, there could be a decrease in MHC expression and an increase in autophagy, combined with suppression of the lymph nodes. Additional details regarding the role of radiotherapy in stimulating the immune system are available in this review [227]. (Created by Biorender.com)

Fig. 6

The main elements involved in the modulation of immunotherapy effectiveness. The effectiveness of immunotherapy is influenced by a complicated interaction of factors that are both intrinsic and extrinsic to the tumor. At the heart of this process is the TME, which differs in immune cell infiltration and immunosuppressive components. Tumor classification and molecular subtypes influence mutational burden and neoantigen generation, with cancers exhibiting high TMB (melanoma, NSCLC) demonstrating improved responses to ICIs. Neoantigens, arising from somatic mutations, play essential roles as targets for T cell-driven anti-tumor immunity. The gut microbiome regulates systemic immune responses, affecting immunotherapy results by means of microbial variety and metabolite generation. Alterations in genes that control antigen presentation, immune checkpoints, and oncogenic pathways also influence immune evasion and resistance to therapy. Moreover, the heterogeneity of the tumor microenvironment and mechanisms of immune evasion (like PD-L1 overexpression and MHC downregulation) result in differing responses. Research is underway on combination therapies aimed at these various factors to address resistance and improve treatment effectiveness. This illustration emphasizes the complex nature of immunotherapy responses and the necessity for tailored treatment approaches. (Created by Biorender.com)

Fig. 7

The targets of small molecules in the field of cancer immunotherapy. Tumor cells are encased by various immune cells, including Tregs, Teffs, MDSCs, TAMs, and DCs. Scientists are exploring various proteins and receptors found on tumor and immune cells as potential targets for cancer immunotherapy. The targets encompass PD-1/PD-L1, RORγt, chemokine receptors, and TGF-β, linked to the adaptive immune response; Sting and TLR, associated with the innate immune response; and IDO, arginase, and A2 A adenosine receptor, which are relevant to the tumor microenvironment. The most promising and therapeutically developed targets consist of immune checkpoint proteins like PD-L1 (found on tumor cells), PD-1 (located on effector T cells), and CTLA4 (present on Tregs). Additional targets being examined in immuno-oncology encompass IDO/TDO and arginases, which play a role in the inherent processes of cancer cells [271]