Nearly a decade after Science named ’cancer immunotherapy’ as the breakthrough of the year 2013 [20], it has seen remarkable advances over the years. Many preclinical studies yielded novel therapies that became successful upon enrollment in clinical trials. Such success is striking in solid tumors [21]. Thus, immunotherapy is a powerful clinical strategy for the treatment of various diseases, including cancer [22], and an understanding of cancer immunology is important to the optimization of this strategy to achieve higher efficacy. For instance, advancements in single-cell RNA sequencing technologies have provided the opportunity to dissect heterogeneous tumor cells. Interrogation of this TME milieu has given clues to the precise nature of tumor-infiltrating cells and other intratumoral immune cells. Moreover, cancer immunotherapy can manipulate the immune system to identify and fight cancer cells, thereby inducing a durable response [23] with the overall aim of providing active or passive immunity against tumors [24]. Over the years, oncologists have depended on only three treatment options: surgical resection, radiotherapy, and chemotherapy. In addition, the use of small molecule inhibitors for certain kinases in many clinical procedures is still an ongoing practice in precision oncology. However, the emergence of immune-based cancer therapy has improved the choice of treatment and cancer management strategies. Since the discovery and use of the first immunotherapy, scientists have developed several other immunotherapies, including immune checkpoint inhibitors (ICIs), adoptive cell transfer, cytokines, vaccines, and others (Figure 1), which are discussed in detail in this section of the review.

The discovery of immune checkpoints, such as CTLA-4 and PD-1, has revolutionized cancer immunotherapy [25]. These checkpoints interact with their cognate ligands on tumors and quell antitumor T cell responses. A paradigm for T cell activation includes an initial presentation of a major histocompatibility complex (MHC)-anchored antigen to T cells, interaction with the co-stimulatory receptor, and cytokine stimulation. Another inhibitory co-receptor exists to provide a negative regulation of T cell activation. These inhibitory co-receptors are checkpoint proteins that can induce adaptive tolerance and T cell exhaustion [26]. Notably, immune checkpoints regulate the tumor-killing effect of immune effector cells. Thus, ICIs can target the dysfunctional immune system to restore the effector function of cytotoxic CD8 T cells [27,28].

The first identified immune checkpoint was CTLA-4 [29]. This receptor usually out-competes another cell surface receptor, CD28, on T cells for their costimulatory ligands, CD80 and CD86. Antibodies targeted against CTLA-4 can enhance T cell response to tumors. Ipilimumab is a monoclonal antibody and the first globally approved anti-CTLA-4 for the first or second line of treatment in patients with malignant melanoma [30]. Apart from the use of ipilimumab as a single-agent monotherapy, it has been used in combination with other therapies for the treatment of various malignancies [31,32,33]. Many combination strategies that can block CTLA-4 or other immune checkpoints have been evaluated in several clinical trials around the globe. Mechanistically, anti-CTLA-4 induces preferential ligation of CD80/CD86 to CD28, leading to T cell activation.

PD-1 is another key checkpoint receptor that can modulate T cell activities in order to promote self-tolerance and activate the senescence of antigen-dependent T cells while preventing the apoptosis of regulatory T cells (Tregs). Cancer cells incessantly explore this mechanism by upregulating PD-L1, a cognate ligand of PD-1. Immunotherapy based on PD-1 blockade has shown promising efficacy in both solid and hematological malignancies [34]. In 2014, the FDA approved anti-PD-1 nivolumab, a fully humanized immunoglobulin G4 monoclonal antibody, for the treatment of advanced melanoma [34,35]. This immunotherapy can transform patient cohorts with microsatellite unstable colorectal cancer [36]. Since its initial approval, nivolumab has been repurposed and approved for the treatment of other malignancies. These include NSCLC, renal cell cancer, Hodgkin’s lymphoma, squamous head and neck cancer, urothelial carcinoma, and HCC [37,38]. More recently, the FDA approved cemiplimab (PD-1 inhibitor) for the first-line treatment of advanced non-small cell lung cancer [39], which has been approved for patients with metastatic cutaneous squamous cell carcinoma (CSCC) or patients with locally advanced CSCC that is not suitable for curative surgery or radiation [40].

Another humanized monoclonal anti-PD1 antibody is pembrolizumab. Following its previous approval for the treatment of NSCLC and unresectable melanoma [41], the U.S. FDA approved this ICI for the treatment of patients with advanced PD-L1-positive gastric and gastroesophageal junction adenocarcinoma who have progressed on at least two lines of chemotherapies [42]. A recent report has shown that pembrolizumab can be used as the first line of treatment for recurrent and metastatic HNSCC [43]. In a clinical trial, pembrolizumab showed safety and efficacy signals in phases 1 and 2 for the treatment of classic Hodgkin’s lymphoma [44].

Immunotherapies that can target the PD-1 ligand, PD-L1, have been developed. Atezolizumab is anti-PD-L1 immunotherapy, and the first ICI approved for the treatment of triple-negative breast cancer [45]. Current preclinical and clinical evidence suggests that atezolizumab may be approved as a single monotherapy or in combination with other therapies for the treatment of various malignancies. In addition to atezolizumab, two additional anti-PD-L1 immunotherapies have been approved. One, durvalumab, was approved for the treatment of urothelial cancer [46] and extensive-stage SCLC patients [47]. The other, namely avelumab, is a human IgG1 approved for the treatment of Merkell cell carcinoma and urothelial carcinoma [48].

Cytokines play an important role in the regulation of innate and adaptive immunity while acting as messengers via autocrine and paracrine signalings over a short distance [49]. Certain antitumor effector functions involving critical aspects of immunity require the release of cytokines or cytokine-mediated activation of antitumor immunity. Over time, scientists have developed an interest in harnessing cytokines for the treatment of cancer.

Interferon alpha (IFN-α) belongs to the family of cytokines. Like other type I IFNs, it signals through the Janus kinase 1 (JAK1) signal transducer and activator of the transcription (STAT) pathway. IFNα polarizes CD4 T cells to T helper type 1 (Th1) effector cells, upregulates MHC class I molecules, and activates caspase-dependent apoptosis in certain cancers. For decades, various formulations of recombinant IFN-α were approved for the treatment of various malignancies, including metastatic renal cell carcinoma, acquired immunodeficiency syndrome (AIDs)-related Kaposi’s sarcoma, follicular lymphoma, chronic myelogenous leukemia, cervical intraperitoneal neoplasms, and completely resected stage III or IV high-risk melanoma [49].

Another universally approved cytokine therapy is interleukin (IL)-2, which is mainly secreted by Th1 effector cells. CD8 T cells and NK cells also secrete IL-2 but to a lesser extent [50]. While acting as a T cell growth factor, IL-2 promotes the expansion of T cells, which is important in the regulation of T cell response and the maintenance of self-tolerance via activation-induced cell death (AICD). IL-2 has been approved for the treatment of metastatic melanoma and metastatic renal cell carcinoma (mRCC). In addition, IL-2 is widely combined with adoptive T cell therapy, as it enhances the ex vivo expansion of T cells [51,52].

Other cytokines, including IFN-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-12, IL-15, and IL-21, have been evaluated for their anticancer potential in preclinical and clinical models. IFN-γ showed an initial promising result in a phase 2 trial but was not approved to treat cancer patients due to the lack of efficacy [53]. In several trials, GM-CSF demonstrated inconsistent efficacy in addition to its scarring effect [54]. With a previous promising phase 1 trial result, IL-12 belied the previous dosing regimen and showed adverse effects and mortality [55]. Further, the antitumor efficacy of IL-15 was evaluated in preclinical studies and phase 1/2 clinical trials. IL-15 activated and caused the expansion of NK, NKT, and (m) CD8 T cells [56]. In another study, the combination of IL-15 with anti-PD-L1 and anti-CTLA4 contributed to favorable OS [57]. Thus, the outcomes from these studies are promising for the future development of IL-15–based therapy. On the other hand, IL-21 plays a critical role in chronic inflammatory bowel disease (IBD) and inflammation-induced colon cancer, thus leading to its termination in the clinical trial [58]. Despite these treatment-related adverse events (TRAEs), there are several ongoing clinical trials to re-evaluate the anti-tumor potentials of these cytokines.

Adoptive cell therapy (ACT) has emerged as an important therapy for cancers, especially personalized cancer therapy [59]. T cells for ACT mainly include tumor-infiltrating lymphocyte-derived T cells or genetically engineered T cells with the expression of conventional T cell receptors or chimeric antigen receptors [60]. Commonly used gene-editing strategies in T cells include retroviral or lentiviral transduction, zinc finger, or transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeat (CRISPR)-associated 9 (Cas9) endonuclease technology [61,62,63].

Chimeric antigen receptor T (CAR-T) cells use a gene transfer technology that involves an ex vivo modification of T cells and an adoptive transfer of the engineered T cells in order to target tumor-associated antigen (TAA) and bolster the antitumor function of T lymphocytes. Although different types of T cells may present different efficacy with a specific CAR technology, various modifications are available to prolong survival and redirect the specificity and function of T cells [64].

In general, CAR-T cells are structurally engineered to contain an extracellular antigen-binding domain derived from a single-chain variable fragment (ScFv) of a monoclonal antibody, an extracellular region containing a spacer domain, a transmembrane domain, and an intracellular domain [65]. Upon antigen binding to the ScFv, the intracellular domain is capable of initiating signaling that culminates in T cell activation. This T cell activation is MHC-independent and can lead to tumor destruction. The success of CAR-T-based immunotherapy depends on the TAA selected for CAR specificity. Usually, the CAR gene is designed to recognize only TAAs that are critical to the survival of the tumor. Despite the promising outcomes of CAR technology, certain tumor genetic mutations and epigenetic alterations are drivers of immunoediting, which can result in therapeutic resistance [66,67].

CAR-T cell-based therapy has shown encouraging efficacies toward hematological malignancies. One major TAA target is CD-19. Kymriah and Yescarta are CD19-targeting CAR-T cell products approved by the U.S. FDA for the standard of care of B cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL), respectively [68,69]. Brexucabtagene autoleucel (brexu-cel) was also approved for the treatment of relapsed or refractory (r/r) mantle cell lymphoma [70]. Other CD-19-directed CAR-T cell products include tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel), which were approved for the treatment of patients with r/r DLBCL, B-ALL, and primary mediastinal B-cell lymphoma (PMBCL) [71,72]. In other tumor types, CAR may be engineered to recognize other antigens. For instance, ganglioside GD2 is a TAA in neuroblastoma [73]; CD70 is a novel target in gliomas [74]; CD20 and CD22 are TAAs in relapsed refractory Burkitt lymphoma [75]. In our previous study, we reported liver-intestine cadherin (CDH17) as a novel target in pancreatic cancer. Our data showed that knockout of CDH17 suppressed Panc02-H7 growth and caused tumor regression in our orthotopic mouse model [76]. As the evolution of CAR technology continues, CDH17 has become a novel TAA for the development of newly engineered CAR T cells. Feng et al., in a 2022 report, demonstrated that CDH17CAR T cells suppressed neuroendocrine and gastrointestinal tumors without TRAEs [77].

The use of oncolytic viruses in the treatment of malignancies is becoming increasingly promising. Oncolytic viruses are genetically modified viruses that can selectively replicate and target cancer cells for destruction without any deleterious effects on normal tissue [78]. Mechanistically, virotherapy induces specific antitumor immunity in the context of tumor-specific viral replication.

The first oncolytic virotherapy, rigvir, was developed from the native ECHO-7 strain of picornavirus. Rigvir was registered in Latvia, Georgia, Armenia, and Uzbekistan, where it was approved for the treatment of melanoma [79]. Furthermore, a genetically engineered adenovirus, oncorine (H101), was approved in November 2005 by the Chinese SFDA as a standard of care for nasopharyngeal carcinoma, but in combination with chemotherapy [80]. Other oncolytic adenovirus therapies that can target and eliminate cancer cells in both preclinical and clinical models have been developed [81,82,83]. However, the efficacy of this therapy is generally challenged by inefficient systemic delivery to the target tissue. This is due to the presence of pre-existing neutralizing antibodies to adenovirus [84] and non-specific uptake [85]. In 2015, a herpes simplex virus type 1 (HSV-1)-based virotherapy was developed. This modified HSV-1, called Talimogene laherparepvec (T-vec), was armed with GM-CSF. Following a phase 3 clinical trial that showed that T-vec significantly caused tumor regression and prolonged the OS of melanoma patients [86], the U.S. FDA approved T-vec for the treatment of unresectable cutaneous, subcutaneous, and nodal lesions in melanoma patients with relapse [78,87].

In addition to the approved virotherapies, at least 40 oncolytic viruses are currently being tested against different cancers [88]. Some of these oncolytic viral therapies have shown promising results in phase 3 clinical trials and are now awaiting approval. These include oncolytic vaccinia virus-derived pexastimogen devbacirepvec (pexa-vec), oncolytic adenovirus-derived CG0070, and oncolytic reovirus-derived reolysin (pelareorep) [89].

Therapeutic cancer vaccines aim to promote tumor regression, establish robust antitumor memory, and avoid adverse events [90]. In principle, cancer vaccines stemmed from the natural phenomenon of antitumor immunity that emerged from natural or chemotherapy-induced immunogenic cell death (ICD). Therapeutic cancer vaccines can be used to treat advanced or relapsed tumors that are refractory to conventional therapies [91]. During ICDs, tumor antigens are released, captured, and cross-presented by APCs, leading to their maturation and migration to secondary lymphoid organs, where they educate naïve T cells. Upon activation, T cells roll back to the TME and cause the direct destruction of cancer cells [92,93].

Cancer vaccines usually contain specific tumor antigens and are exogenously administered to activate APCs such as DCs, leading to the stimulation of an adaptive immune response against tumors containing this antigen and the resurgence of robust tumor control. Usually, large amounts of qualitative antigens are delivered to the DCs to induce optimal DC activation, culminating in sustained T cell activation, TME infiltration, and response maintenance [90]. Alternatively, it is possible to develop a cancer vaccine from an endogenous source, a method called the in situ (ISV) approach. It involves antigen sourcing from dying or dead cells in the TME [94].

Neoantigens derived from tumor mutations have been recognized as ideal targets of T cell-based immunotherapy and therapeutic cancer vaccines [95,96]. Neoantigen-targeted vaccines mainly include synthetic long peptides, nucleic acids, and cell-based vaccines [97]. Currently, many clinical trials have evaluated their safety and efficacy in patients [98,99]. Examples of some vaccines are discussed in the section on clinical trials.

Sipuleucel-T is an antigen-specific active immunotherapy agent that sensitizes the adaptive immune system [100] by activating the anti-PAP (prostatic acid phosphatase) immune response, leading to the destruction of cancer cells [101]. The U.S. FDA approved Sipuleucel-T after a double-blind, placebo-controlled, multicenter phase 3 trial in which Sipuleucel-T reduced the risk of death among patients with metastatic castration-resistant prostate cancer (mCRPC) [102]. Although Sipuleucel-T remains the only cancer vaccine approved, other cancer vaccines are currently being investigated. For instance, four cancer vaccines have been tested in phase 3 clinical trials of mCRPC patients. These include prostate cancer vaccine GVAX (a GM-CSF gene vaccine), anti-prostate-specific antigen (PSA) vaccine PROSTVAC, personalized peptide vaccination (PPV), and DC-based vaccine PCVAC/PCa [101].

In summary, immunotherapy has provided a powerful tool for cancer therapy, either alone or as a synergistic treatment. Some examples of FDA-approved treatments are listed in Table 1.