Combination of tumor antigen drainage and immune activation to promote a cancer-immunity cycle against glioblastoma.

While conventional cancer modalities, such as chemotherapy and radiotherapy, act through direct killing of tumor cells, cancer immunotherapy elicits potent anti-tumor immune responses thereby eliminating tumors. Nevertheless, promising outcomes have not been reported in patients with glioblastoma (GBM) likely due to the immune privileged status of the central nervous system and immunosuppressive micro-environment within GBM. In the past years, several exciting findings, such as the re-discovery of meningeal lymphatic vessels (MLVs), three-dimensional anatomical reconstruction of MLV networks, and the demonstration of the promotion of GBM immunosurveillance by lymphatic drainage enhancement, have revealed an intricate communication between the nervous and immune systems, and brought hope for the development of new GBM treatment. Based on conceptual framework of the updated cancer-immunity (CI) cycle, here we focus on GBM antigen drainage and immune activation, the early events in driving the CI cycle. We also discuss the implications of these findings for developing new therapeutic approaches in tackling fatal GBM in the future.

Activating Iterative Revolutions of the Cancer-Immunity Cycle in Hypoxic Tumors with a Smart Nano-Regulator.

The activation of sequential events in the cancer-immunity cycle (CIC) is crucial for achieving effective antitumor immunity. However, formidable challenges, such as innate and adaptive immune resistance, along with the off-target adverse effects of nonselective immunomodulators, persist. In this study, a tumor-selective nano-regulator named PNBJQ has been presented, focusing on targeting two nonredundant immune nodes: inducing immunogenic cancer cell death and abrogating immune resistance to fully activate endogenous tumor immunity. PNBJQ is obtained by encapsulating the immunomodulating agent JQ1 within a self-assembling system formed by linking a Type-I photosensitizer to polyethylene glycol through a hypoxia-sensitive azo bond. Benefiting from the Type-I photosensitive mechanism, PNBJQ triggers the immunogenic cell death of hypoxic tumors under near-infrared (NIR) light irradiation. This process resolves innate immune resistance by stimulating sufficient cytotoxic T-lymphocytes. Simultaneously, PNBJQ smartly responds to the hypoxic tumor microenvironment for precise drug delivery, adeptly addressing adaptive immune resistance by using JQ1 to downregulate programmed death ligand 1 (PD-L1) and sustaining the response of cytotoxic T lymphocytes. The activatable synergic photoimmunotherapy promotes an immune-promoting tumor microenvironment by activating an iterative revolution of the CIC, which remarkably eradicates established hypoxic tumors and suppresses distal lesions under low light dose irradiation.

Syringeable Near-Infrared Light-Activated In Situ Immunogenic Hydrogel Boosts the Cancer-Immunity Cycle to Enhance Anticancer Immunity.

Effective anticancer immunity depends on properly activating multiple stepwise events in the cancer-immunity cycle. An immunologically "cold" tumor microenvironment (TME) engenders immune evasion and refractoriness to conventional checkpoint blockade immunotherapy. Here, we combine nanoparticle formulations and an in situ formed hydrogel scaffold to treat accessible tumors locally and to stimulate systemic immunity against metastatic tumor lesions. The nanoparticles encapsulate poly(ε-caprolactone)-derived cytotoxic chemotherapy and adjuvant of Toll-like receptor 7/8 through a reactive oxygen species (ROS)-cleavable linker that can be self-activated by the coassembled neighboring photosensitizer following near-infrared (NIR) laser irradiation. Further development results in syringeable, NIR light-responsive, and immunogenic hydrogel (iGEL) that can be implanted peritumorally and deposited into the tumor surgical bed. Upon NIR laser irradiation, the generated ROS induces iGEL degradation and bond cleavage in the polymer-drug conjugates, triggering the immunogenic cell death cascade in cancer cells and spontaneously releasing encapsulated agents to rewire the cancer-immunity cycle. Notably, upon application in multiple preclinical models of melanoma and triple-negative breast cancer, which are aggressive and refractory to conventional immunotherapy, iGEL induces durable remission of established tumors, extends postsurgical tumor-free survival, and inhibits metastatic burden. The result of this study is a locally administrable immunogenic hydrogel for triggering host systemic immunity to improve immunotherapeutic efficacy with minimal off-target side effects.

Individualized Multimodal Immunotherapy (IMI): Scientific Rationale and Clinical Experience from a Single Institution.

Oncolytic viruses and combinatorial immunotherapy for cancer (this Special Issue) are both part of cancer treatment at IOZK. This review focusses on an individual multimodal cancer immunotherapy concept developed by IOZK, Cologne, Germany. The scientific rationale for employing three main components is explained: (i) oncolytic Newcastle disease virus, (ii) modulated electrohyperthermia and (iii) individual tumor antigen and oncolytic virus modified dendritic cell vaccine (IO-VACR). The strategy involves repeated cancer-immunity cycles evoked in cancer patients by systemic oncolytic virus exposure plus hyperthermia pretreatment to induce immunogenic cell death followed by intradermal IO-VACR vaccination. As an example of the experience at IOZK, we present the latest results from combining the immunotherapy with standard treatment of patients suffering from glioblastoma multiforme. The promising clinical results in terms of overall survival benefit of additional individualized multimodal immunotherapy are presented. The cancer-immunity cycle, as introduced 10 years ago, describes key important steps occurring locally at the sites of both tumor and draining lymph nodes. This view is extended here towards systemic events occuring in blood where immunogenic cell death-induced tumor antigens are transported into the bone marrow. For 20 years it has been known that bone marrow is an antigen-responsive organ in which dendritic cells present tumor antigens to T cells leading to immunological synapse formation, tumor antigen-specific T cell activation and memory T cell formation. Bone marrow is known to be the most prominent source of de novo cellular generation in the body and to play an important role for the storage and maintenance of immunological memory. Its systemic activation is recommended to augment cancer-immunity cycles.

Immunological Mechanisms behind Anti-PD-1/PD-L1 Immune Checkpoint Blockade: Intratumoral Reinvigoration or Systemic Induction?

Anti-PD-1/PD-L1 immune checkpoint blockade (ICB) has been widely used to treat many types of cancer. It is well established that PD-L1 expressing cancer cells could directly inhibit the cytotoxicity of PD-1+ T cells via PD-L1-PD-1 interaction. However, histological quantification of intratumoral PD-L1 expression provides limited predictive value and PD-L1 negative patients could still benefit from ICB treatment. Therefore, the current major clinical challenges are low objective response rate and unclear immunological mechanisms behind responding vs. non-responding patients. Here, we review recent studies highlighting the importance of longitudinal pre- and post-ICB treatment on patients with various types of solid tumor to elucidate the mechanisms behind ICB treatment. On one hand, ICB induces changes in the tumor microenvironment by reinvigorating intratumoral PD-1+ exhausted T cells ("releasing the brakes"). On the other hand, ICB can also affect systemic antitumor immunity in the tumor-draining lymph node to induce priming/activation of cancer specific T cells, which is evident by T cell clonal expansion/replacement in peripheral blood. These studies reveal that ICB treatment not only acts on the tumor microenvironment ("battlefield") but also acts on immune organs ("training camp") of patients with solid tumors. A deeper understanding of the immunological mechanisms behind ICB treatment will pave the way for further improvements in clinical response.

Cancer immunometabolism: advent, challenges, and perspective.

For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role.

Advances in traditional Chinese herbal medicine and their pharmacodynamic mechanisms in cancer immunoregulation: a narrative review.

Background and Objective: The cancer-immunity cycle (CIC) is defined as a series of progressive events that cause an anticancer immune response leading to the killing of the cancer cell. The concept of CIC has important guiding significance for the clinical and basic tumor immunotherapy research. As one of the methods of traditional Chinese medicine (TCM), Chinese herbal medicine (CHM) has shown unique advantages in multitarget and multipathway immune regulation. However, the tumor immune circulation targeted by CHM is generally unclear at present. To provide reference for future clinical and basic research, we systematically reviewed the existing literature on CHM (including CHM monomers, CHM compounds, and CHM patent medicines) and the mechanisms related to its efficacy. Methods: We searched the PubMed and China National Knowledge Infrastructure (CNKI) databases for relevant Chinese-language and English-language literature published from January 1988 to October 2022. The literature was screened manually at three levels: title, abstract, and full text, to identify articles related to CHM and their mechanism of regulating tumor immunity. Key Content and Findings: By further classifying the CIC, it was confirmed that CHM can regulate the activation of dendritic cells (DCs) and macrophages and promote the presentation of tumor antigens. Meanwhile, CHM can also reverse tumor-immune escape by enhancing T-cell proliferation and infiltration. In addition, CHM can also enhance the antitumor ability of the body by regulating the killing process of tumor cells. Conclusions: The theory of a CIC is of guiding significance to regulating tumor immunity via CHM.

Modulator of TMB-associated immune infiltration (MOTIF) predicts immunotherapy response and guides combination therapy.

Patients with high tumor mutational burden (TMB) levels do not consistently respond to immune checkpoint inhibitors (ICIs), possibly because a high TMB level does not necessarily result in adequate infiltration of CD8+ T cells. Using bulk ribonucleic acid sequencing (RNA-seq) data from 9311 tumor samples across 30 cancer types, we developed a novel tool called the modulator of TMB-associated immune infiltration (MOTIF), which comprises genes that can determine the extent of CD8+ T cell infiltration prompted by a certain TMB level. We confirmed that MOTIF can accurately reflect the integrity and defects of the cancer-immunity cycle. By analyzing 84 human single-cell RNA-seq datasets from 32 types of solid tumors, we revealed that MOTIF can provide insights into the diverse roles of various cell types in the modulation of CD8+ T cell infiltration. Using pretreatment RNA-seq data from 13 ICI-treated cohorts, we validated the use of MOTIF in predicting CD8+ T cell infiltration and ICI efficacy. Among the components of MOTIF, we identified EMC3 as a negative regulator of CD8+ T cell infiltration, which was validated via in vivo studies. Additionally, MOTIF provided guidance for the potential combinations of programmed death 1 blockade with certain immunostimulatory drugs to facilitate CD8+ T cell infiltration and improve ICI efficacy.

Comprehending the cuproptosis and cancer-immunity cycle network: delving into the immune landscape and its predictive role in breast cancer immunotherapy responses and clinical endpoints.

Background: The role of cuproptosis, a phenomenon associated with tumor metabolism and immunological identification, remains underexplored, particularly in relation to the cancer-immunity cycle (CIC) network. This study aims to rigorously examine the impact of the cuproptosis-CIC nexus on immune reactions and prognostic outcomes in patients with breast cancer (BC), striving to establish a comprehensive prognostic model. Methods: In the study, we segregated data obtained from TCGA, GEO, and ICGC using CICs retrieved from the TIP database. We constructed a genetic prognostic framework using the LASSO-Cox model, followed by its validation through Cox proportional hazards regression. This framework's validity was further confirmed with data from ICGC and GEO. Explorations of the tumor microenvironment were carried out through the application of ESTIMATE and CIBERSORT algorithms, as well as machine learning techniques, to identify potential treatment strategies. Single-cell sequencing methods were utilized to delineate the spatial distribution of key genes within the various cell types in the tumor milieu. To explore the critical role of the identified CICs, experiments were conducted focusing on cell survival and migration abilities. Results: In our research, we identified a set of 4 crucial cuproptosis-CICs that have a profound impact on patient longevity and their response to immunotherapy. By leveraging these identified CICs, we constructed a predictive model that efficiently estimates patient prognoses. Detailed analyses at the single-cell level showed that the significance of CICs. Experimental approaches, including CCK-8, Transwell, and wound healing assays, revealed that the protein HSPA9 restricts the growth and movement of breast cancer cells. Furthermore, our studies using immunofluorescence techniques demonstrated that suppressing HSPA9 leads to a notable increase in ceramide levels. Conclusion: This research outlines a network of cuproptosis-CICs and constructs a predictive nomogram. Our model holds great promise for healthcare professionals to personalize treatment approaches for individuals with breast cancer. The work provides insights into the complex relationship between the cuproptosis-CIC network and the cancer immune microenvironment, setting the stage for novel approaches to cancer immunotherapy. By focusing on the essential gene HSPA9 within the cancer-immunity cycle, this strategy has the potential to significantly improve the efficacy of treatments against breast cancer.

Immunogram defines four cancer-immunity cycle phenotypes with distinct clonal selection patterns across solid tumors.

BACKGROUND: The cancer-immunity cycle (CI cycle) provides a theoretical framework to illustrate the process of the anticancer immune response. Recently, the update of the CI cycle theory emphasizes the importance of tumor's immunological phenotype. However, there is lack of immunological phenotype of pan-cancer based on CI cycle theory. METHODS: Here, we applied a visualizing method termed 'cancer immunogram' to visualize the state of CI cycle of 8460 solid tumors from TCGA cohort. Unsupervised clustering of the cancer immunogram was performed using the nonnegative matrix factorization (NMF) analysis. We applied an evolutionary genomics approach (dN/dS ratio) to evaluate the clonal selection patterns of tumors with distinct immunogram subtypes. RESULTS: We defined four major CI cycle patterns across 32 cancer types using a cancer immunogram approach. Immunogram-I was characterized by 'hot' and 'exhausted' features, indicating a favorable prognosis. Strikingly, immunogram-II, immunogram-III, and immunogram-IV represented distinct immunosuppressive patterns of 'cold' tumor. Immunogram-II was characterized by 'cold' and 'radical' features, which represented increased expression of immune inhibitor molecules and high levels of positive selection, indicating the worst prognosis. Immunogram-III was characterized by 'cold' and 'recognizable' features and upregulated expression of MHC I molecules. Immunogram-IV was characterized by 'cold' and 'inert' features, which represented overall immunosuppression, lower levels of immunoediting and positive selection, and accumulation of more tumor neoantigens. In particular, favorable overall survival was observed in metastatic urothelial cancer patients with immunogram-I and immunogram-IV after immune checkpoint inhibitor (ICI) therapy. Meanwhile, a higher response rate to ICI therapy was observed in metastatic gastric cancer patients with immunogram-I phenotype. CONCLUSIONS: Our findings provide new insight into the interaction between immunity and cancer evolution, which may contribute to optimizing immunotherapy strategies.

Lipid-based nanoparticles for cancer immunotherapy.

As the fourth most important cancer management strategy except surgery, chemotherapy and radiotherapy, cancer immunotherapy has been confirmed to elicit durable antitumor effects in the clinic by leveraging the patient's own immune system to eradicate the cancer cells. However, the limited population of patients who benefit from the current immunotherapies and the immune related adverse events hinder its development. The immunosuppressive microenvironment is the main cause of the failure, which leads to cancer immune evasion and immunity cycle blockade. Encouragingly, nanotechnology has been engineered to enhance the efficacy and reduce off-target toxicity of their therapeutic cargos by spatiotemporally controlling the biodistribution and release kinetics. Among them, lipid-based nanoparticles are the first nanomedicines to make clinical translation, which are now established platforms for diverse areas. In this perspective, we discuss the available lipid-based nanoparticles in research and market here, then describe their application in cancer immunotherapy, with special emphasis on the T cells-activated and macrophages-targeted delivery system. Through perpetuating each step of cancer immunity cycle, lipid-based nanoparticles can reduce immunosuppression and promote drug delivery to trigger robust antitumor response.

Combination Therapy of Immune Checkpoint Inhibitors with Locoregional Therapy for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is estimated to be the fourth leading cause of cancer-related deaths globally, and its overall prognosis is dismal because most cases are diagnosed at a late stage and are unamenable to curative treatment. The emergence of immune checkpoint inhibitors (ICIs) has dramatically improved the therapeutic efficacy for advanced hepatocellular carcinoma; however, their response rates remain unsatisfactory, partly because >50% of HCC exhibit an ICI-nonresponsive tumor microenvironment characterized by a paucity of cytotoxic T cells (immune-cold), as well as difficulty in their infiltration into tumor sites (immune excluded). To overcome this limitation, combination therapies with locoregional therapies, including ablation, transarterial embolization, and radiotherapy, which are usually used for early stage HCCs, have been actively explored to enhance ICI efficacy by promoting the release of tumor-associated antigens and cytokines, and eventually accelerating the so-called cancer-immunity cycle. Various combination therapies have been investigated in early- to late-phase clinical trials, and some have shown promising results. This comprehensive article provides an overview of the immune landscape for HCC to understand ICI efficacy and its limitations and, subsequently, reviews the status of combinatorial therapies of ICIs with locoregional therapy for HCC.

Identification of TUBB2A as a Cancer-Immunity Cycle-Related Therapeutic Target in Triple-Negative Breast Cancer.

OBJECTIVE: Triple negative breast cancer (TNBC) is a malignant subtype of breast cancer characterized by the absence of ER, PR, and HER2. We aimed to explore target gene from the perspective of cancer-immunity cycle, providing insights into treatment of TNBC. METHODS: We obtained TNBC samples from METABRIC database and downloaded 4 datasets from GEO database, as well as an IMvigor210 dataset. WGCNA was applied to screen genes associated with cancer-immunity cycle in TNBC. GO, KEGG and GSEA analyses were performed to explore the target gene's potential functions and pathways. The binding motifs with transcription factors were predicted with FIMO. Immune infiltration analysis was conducted by CIBERSORT. RESULTS: TUBB2A was screened out as our target gene which was negatively correlated with T cell recruitment in cancer-immunity cycle. TUBB2A expressed higher in TNBC samples than in normal samples. High expression of TUBB2A was associated with poor prognosis of TNBC. 12 transcription factors and 5 miRNAs might regulate TUBB2A's expression. The infiltration ratios of 7 types of immune cells such as CD8+ T cells, naive CD4+ T cells and activated memory CD4+ T cells were significantly lower in TUBB2A high expression group. TUBB2A was a potential drug target. CONCLUSION: We screened a cancer-immunity cycle-related gene TUBB2A which was negatively correlated with T cell recruiting in TNBC. TUBB2A expressed higher in TNBC samples than in normal samples, associated with poor prognosis.

Strategies to synergize PD-1/PD-L1 targeted cancer immunotherapies to enhance antitumor responses in ovarian cancer.

Anti-programmed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) antibodies have developed rapidly but exhibited modest activity in ovarian cancer (OC), achieving a clinical response rate ranging from 5.9% to 19%. Current evidence indicate that the establishment of an integrated cancer-immunity cycle is a prerequisite for anti-PD-1/PD-L1 antibodies. Any impairment in this cycle, including lack of cancer antigens release, impaired antigen-presenting, decreased T cell priming and activation, less T cells that are trafficked or infiltrated in tumor microenvironment (TME), and low tumor recognition and killings, will lead to decreased infiltrated cytotoxic T cells to tumor bed and treatment failure. Therefore, combinatorial strategies aiming to modify cancer-immunity cycle and reprogram tumor immune microenvironment are of great interest. By far, various strategies have been studied to enhance responsiveness to PD-1/PD-L1 inhibitors in OC. Platinum-based chemotherapy increases neoantigens release; poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) improve the function of antigen-presenting cells and promote the trafficking of T cells into tumors; epigenetic drugs help to complete the immune cycle by affecting multiple steps; immunotherapies like anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies reactivate T cells, and other treatment strategies like radiotherapy helps to increase the expression of tumor antigens. In this review, we will summarize the preclinical studies by analyzing their contribution in modifying the cancer immunity cycle and remodeling tumor environment, and we will also summarize recent progress in clinical trials and discuss some perspectives to improve these treatment strategies.

Exhausted T cells hijacking the cancer-immunity cycle: Assets and liabilities.

T cell exhaustion is an alternative differentiation path of T cells, sometimes described as a dysfunction. During the last decade, insights of T cell exhaustion acting as a bottle neck in the field of cancer immunotherapy have undoubtedly provoked attention. One of the main drivers of T cell exhaustion is prolonged antigen presentation, a prerequisite in the cancer-immunity cycle. The umbrella term "T cell exhaustion" comprises various stages of T cell functionalities, describing the dynamic, one-way exhaustion process. Together these qualities of T cells at the exhaustion continuum can enable tumor clearance, but if the exhaustion acquired timeframe is exceeded, tumor cells have increased possibilities of escaping immune system surveillance. This could be considered a tipping point where exhausted T cells switch from an asset to a liability. In this review, the contrary role of exhausted T cells is discussed.

Carrier-free delivery of thymopentin-regulated injectable nanogels via an enhanced cancer immunity cycle against melanoma metastasis.

Thymopentin (TP5), a clinically used immunomodulatory pentapeptide, can efficiently promote thymocyte differentiation and influence mature T-cell function, thus playing an essential role in the cancer immunotherapy. However, the excellent water solubility and high IC50 of TP5 result in an uncontrolled release behavior, requiring a high loading efficiency to achieve high dosage. Here in, we reported that TP5, combined with specific chemotherapeutic agents, can co-assemble into nanogels due to multiple hydrogen bonding sites. The co-assembly of TP5 with chemotherapeutic agent doxorubicin (DOX) into a carrier-free and injectable chemo-immunotherapy nanogel can enhance the cancer immunity cycle against melanoma metastasis. In this study, the designed nanogel guarantees high drug loading of TP5 and DOX and ensures a site-specific and controlled release of TP5 and DOX with minimal side effects, thus addressing the bottlenecks encountered by current chemo-immunotherapy. Moreover, the released DOX can effectively induce tumor cell apoptosis and immunogenic cell death (ICD) to activate immune initiation. Meanwhile, TP5 can significantly promote the proliferation and differentiation of dendritic cells (DCs) and T lymphocytes to amplify the cancer immunity cycle. As a result, this nanogel shows excellent immunotherapeutic efficacy against melanoma metastasis, as well as an effective strategy for TP5 and DOX application.

Strategies involving STING pathway activation for cancer immunotherapy: Mechanism and agonists.

Recent studies have expanded the known functions of cGAS-STING in inflammation to a role in cancer due to its participation in activating immune surveillance. In cancer cells, the cGAS-STING pathway can be activated by cytosolic dsDNA derived from genomic, mitochondrial and exogenous origins. The resulting immune-stimulatory factors from this cascade can either attenuate tumor growth or recruit immune cells for tumor clearance. Furthermore, STING-IRF3-induced type I interferon signaling can enforce tumor antigen presentation on dendritic cells and macrophages and thus cross-prime CD8+ T cells for antitumor immunity. Given the functions of the STING pathway in antitumor immunity, multiple strategies are being developed and tested with the rationale of activating STING in tumor cells or tumor-infiltrating immune cells to elicit immunostimulatory effects, either alone or in combination with a range of established chemotherapeutic and immunotherapeutic regimens. Based on the canonical molecular mechanism of STING activation, numerous strategies for inducing mitochondrial and nuclear dsDNA release have been used to activate the cGAS-STING signaling pathway. Other noncanonical strategies that activate cGAS-STING signaling, including the use of direct STING agonists and STING trafficking facilitation, also show promise in type I interferon release and antitumor immunity priming. Here, we review the key roles of the STING pathway in different steps of the cancer-immunity cycle and characterize the canonical and noncanonical mechanisms of cGAS-STING pathway activation to understand the potential of cGAS-STING agonists for cancer immunotherapy.

The impact of lipids on the cancer-immunity cycle and strategies for modulating lipid metabolism to improve cancer immunotherapy.

Lipids have been found to modulate tumor biology, including proliferation, survival, and metastasis. With the new understanding of tumor immune escape that has developed in recent years, the influence of lipids on the cancer-immunity cycle has also been gradually discovered. First, regarding antigen presentation, cholesterol prevents tumor antigens from being identified by antigen presenting cells. Fatty acids reduce the expression of major histocompatibility complex class I and costimulatory factors in dendritic cells, impairing antigen presentation to T cells. Prostaglandin E2 (PGE2) reduce the accumulation of tumor-infiltrating dendritic cells. Regarding T-cell priming and activation, cholesterol destroys the structure of the T-cell receptor and reduces immunodetection. In contrast, cholesterol also promotes T-cell receptor clustering and relative signal transduction. PGE2 represses T-cell proliferation. Finally, regarding T-cell killing of cancer cells, PGE2 and cholesterol weaken granule-dependent cytotoxicity. Moreover, fatty acids, cholesterol, and PGE2 can improve the activity of immunosuppressive cells, increase the expression of immune checkpoints and promote the secretion of immunosuppressive cytokines. Given the regulatory role of lipids in the cancer-immunity cycle, drugs that modulate fatty acids, cholesterol and PGE2 have been envisioned as effective way in restoring antitumor immunity and synergizing with immunotherapy. These strategies have been studied in both preclinical and clinical studies.

Immunotherapies: How Do They Work?

The understanding of the immune system and the discovery of the proteins and processes involved in its regulation have enabled the emergence of new approaches against cancer. The development of antibodies (immune checkpoint inhibitors) able of blocking interactions that suppress the activation of T cells or their effector actions against cancer cells has modified the prognosis of several cancer forms. Bispecific antibodies as well as cellular immunotherapies (CARs/TILs) are new immunotherapy approaches that have already shown their effectiveness in certain onco-haematological diseases. Unfortunately, only a fraction of treated patients derives benefit from these treatments. The future challenge will be to understand the resistance mechanisms to immunotherapies so that treatment may be personalized for each patient.

The mutual relationship between the host immune system and radiotherapy: stimulating the action of immune cells by irradiation.

The effects of irradiation on tumor tissue and the host immune system are interrelated. The antitumor effect of irradiation is attenuated in the immunocompromised hosts. In addition, radiation alone positively and negatively influences the host immune system. The positive effects of radiation are summarized by the ability to help induce and enhance tumor-antigen-specific immune responses. The cancer-immunity cycle is a multistep framework that illustrates how the tumor-antigen-specific immune responses are induced and how the induced antigen-specific immune cells exert their functions in tumor tissues. Irradiation affects each step of this cancer-immunity cycle, primarily in a positive manner. In contrast, radiation also has negative effects on the immune system. The first is that irradiation has the possibility to kill irradiated effector immune cells. The second is that irradiation upregulates immunosuppressive molecules in the tumor microenvironment, whereas the third is that irradiation to the tumor condenses immunosuppressor cells in the tumor microenvironment. When used in conjunction with radiotherapy, immune checkpoint inhibitors can further leverage the positive effects of radiation on the immune system and compensate for the negative effects of irradiation, which supports the rationale for the combination of radiotherapy and immune checkpoint inhibitors. In this review, we summarize the preclinical evidence for the reciprocal effects of radiation exposure and the immune system, and up-front topics of the combination therapy of immune checkpoint inhibitors and radiotherapy.