Harnessing the potential of HLA-G in cancer therapy: advances, challenges, and prospects.

Immune checkpoint blockades have been prized in circumventing and ablating the impediments posed by immunosuppressive receptors, reaching an exciting juncture to be an innovator in anticancer therapy beyond traditional therapeutics. Thus far, approved immune checkpoint blockades have principally targeted PD-1/PD-L1 and CTLA-4 with exciting success in a plethora of tumors and yet are still trapped in dilemmas of limited response rates and adverse effects. Hence, unveiling new immunotherapeutic targets has aroused immense scientific interest in the hope of expanding the clinical application of immune checkpoint blockades to scale new heights. Human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, is enriched on various malignant cells and is involved in the hindrance of immune effector cells and the facilitation of immunosuppressive cells. HLA-G stands out as a crucial next-generation immune checkpoint showing great promise for the benefit of cancer patients. Here, we provide an overview of the current understanding of the expression pattern and immunological functions of HLA-G, as well as its interaction with well-characterized immune checkpoints. Since HLA-G can be shed from the cell surface or released by various cells as free soluble HLA-G (sHLA-G) or as part of extracellular vesicles (EVs), namely HLA-G-bearing EVs (HLA-GEV), we discuss the potential of sHLA-G and HLA-GEV as predictive biomarkers. This review also addresses the advancement of HLA-G-based therapies in preclinical and clinical settings, with a focus on their clinical application in cancer.

Immune checkpoint blockades in gynecological cancers: A review of clinical trials.

Advanced and recurrent gynecological cancers are associated with a poor prognosis and there is still a lack of effective treatments. Immune checkpoint blockade (ICB) therapy is an important element of cancer-targeted therapy and immunotherapy. The programed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) pathways are the two main targets of ICB. In this study, we provide a comprehensive review of clinical evidence concerning ICB therapy in gynecological cancers and discuss future implications. All clinical trials of ICB therapy in gynecological cancers were reviewed. We searched ClinicalTrials.gov to collect data from completed and ongoing clinical trials. The clinical evidence regarding the efficacy of ICB agents in gynecological cancers were discussed. Six phase III clinical trials have reported their results of primary outcomes, and a total of 25 phase II clinical trials have been completed. As revealed in phase III trials, pembrolizumab (a PD-1 antibody) improved the overall survival and progression-free survival in endometrial cancer patients with mismatch repair deficiency and cervical cancer patients with expressions of PD-L1. Based on these findings, pembrolizumab was approved by the Food and Drug Administration and European Medicines Agency as a cancer medication used to treat certain patients with endometrial cancer or cervical cancer. Other PD-1 antibodies, including dostarlimab and cemiplimab, also showed antitumor efficacy in clinical trials. Dostarlimab treatment showed an encouraging response rate in endometrial cancer patients with mismatch repair deficiency. Cemiplimab treatment led to a longer overall survival and a lower risk of death than chemotherapy among patients with recurrent cervical cancer. Three completed phase III trials investigated anti-PD-L1 agents (atezolizumab and avelumab) in the treatment of ovarian cancer. The results were not encouraging. Other strategies of ICB therapy which had showed potential clinical benefit in the treatment of gynecological cancers in early-phase trials need to be further evaluated in late-stage trials. The antitumor efficacy of ICB therapy is promising, and the key to making further progress in the treatment of gynecological cancers is to identify more biomarkers and explore innovative combination treatments with other targeted therapies.

The implications of clinical risk factors, CAR index, and compositional changes of immune cells on hyperprogressive disease in non-small cell lung cancer patients receiving immunotherapy.

BACKGROUND: Immune checkpoint blockades (ICBs) are characterized by a durable clinical response and better tolerability in patients with a variety of advanced solid tumors. However, we not infrequently encounter patients with hyperprogressive disease (HPD) exhibiting paradoxically accelerated tumor growth with poor clinical outcomes. This study aimed to investigate implications of clinical factors and immune cell composition on different tumor responses to immunotherapy in patients with non-small cell lung cancer (NSCLC). METHODS: This study evaluated 231 NSCLC patients receiving ICBs between January 2014 and May 2018. HPD was defined as a > 2-fold tumor growth kinetics ratio during ICB therapy and time-to-treatment failure of ≤2 months. We analyzed clinical data, imaging studies, periodic serologic indexes, and immune cell compositions in tumors and stromata using multiplex immunohistochemistry. RESULTS: Of 231 NSCLC patients, PR/CR and SD were observed in 50 (21.6%) and 79 (34.2%) patients, respectively and 26 (11.3%) patients met the criteria for HPD. Median overall survival in poor response groups (HPD and non-HPD PD) was extremely shorter than disease-controlled group (SD and PR/CR) (5.5 and 6.1 months vs. 16.2 and 18.3 months, respectively, P = 0.000). In multivariate analysis, HPD were significantly associated with heavy smoker (p = 0.0072), PD-L1 expression ≤1% (p = 0.0355), and number of metastatic site ≥3 (p = 0.0297). Among the serologic indexes including NLR, PLR, CAR, and LDH, only CAR had constantly significant correlations with HPD at the beginning of prior treatment and immunotherapy, and at the 1st tumor assessment. The number of CD4+ effector T cells and CD8+ cytotoxic T cells, and CD8+/PD-1+ tumor-infiltrating lymphocytes (TIL) tended to be smaller, especially in stromata of HPD group. More M2-type macrophages expressing CD14, CD68 and CD163 in the stromal area and markedly fewer CD56+ NK cells in the intratumoral area were observed in HPD group. CONCLUSIONS: Our study suggests that not only clinical factors including heavy smoker, very low PD-L1 expression, multiple metastasis, and CAR index, but also fewer CD8+/PD-1+ TIL and more M2 macrophages in the tumor microenvironment are significantly associated with the occurrence of HPD in the patients with advanced/metastatic NSCLC receiving immunotherapy.

Sequential and Timely Combination of a Cancer Nanovaccine with Immune Checkpoint Blockade Effectively Inhibits Tumor Growth and Relapse.

We describe a small lipid nanoparticle (SLNP)-based nanovaccine platform and a new combination treatment regimen. Tumor antigen-displaying, CpG adjuvant-embedded SLNPs (OVAPEP -SLNP@CpG) were prepared from biocompatible phospholipids and a cationic cholesterol derivative. The resulting nanovaccine showed highly potent antitumor efficacy in both prophylactic and therapeutic E.G7 tumor models. However, this vaccine induced T cell exhaustion by elevating PD-L1 expression, leading to tumor recurrence. Thus, the nanovaccine was combined with simultaneous anti-PD-1 antibody treatment, but the therapeutic efficacy of this regimen was comparable to that of the nanovaccine alone. Finally, mice that showed a good therapeutic response after the first cycle of immunization with the nanovaccine underwent a second cycle together with anti-PD-1 therapy, resulting in suppression of tumor relapse. This suggests that the antitumor efficacy of combinations of nanovaccines with immune checkpoint blockade therapy is dependent on treatment sequence and the timing of each modality.

Hybrid Nanoreactors: Enabling an Off-the-Shelf Strategy for Concurrently Enhanced Chemo-immunotherapy.

Immunosuppressive tumors generally exhibit poor response to immune checkpoint blockade based cancer immunotherapy. Rationally designed hybrid nanoreactors are now presented that have integrated functions as Fenton catalysts and glutathione depletion agents for amplifying the immunogenic cell death and activating immune cells. A simple physical mixture of nanoreactors and chemodrugs in combination with immune checkpoint blockades show synergistically and concurrently enhanced chemo-immunotherapy efficacy, inhibiting the growth of both treated primary immunosuppressive tumors and untreated distant tumors. The off-the-shelf strategy uses tumor antigens generated in situ and avoids cargo loading, and is thus a substantial advance in personalized nanomedicine for clinical translation.

IL-6 and PD-L1 blockade combination inhibits hepatocellular carcinoma cancer development in mouse model.

Limited efficacy of immune checkpoint inhibitors in hepatocellular carcinoma (HCC) was observed in clinical trials, thus prompting investigation into combination therapy. Interleukin-6 (IL-6) has important roles in modeling immune responses in cancers. Here, we hypothesized that IL-6 blockade would enhance antitumor immunity of HCC and synergize with anti-programmed death-1-ligand 1 (PD-L1) checkpoint inhibitor in treating HCC. The sources and immune modulating effects of IL-6 were investigated in HCC models. Combination of anti-IL-6 and anti-PD-L1 was tested in HCC bearing mice. We found that IL-6 is mainly secreted by cancer associated fibroblast (CAFs), but not tumor cells in HCC. High IL-6 expression CAFs could induce strong immunosuppression in HCC microenvironment by recruiting immunosuppressive cells, such as myeloid derived suppressive cells. In addition, high IL-6 expression CAFs also impaired tumor infiltrating T-cell function via upregulating inhibitory immune checkpoints. Using IL-6 blockade could reverse anti-PD-L1 resistance in HCC tumor model. In conclusion, our study indicates that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in HCC, providing a potential strategy to overcoming anti-PD-L1 resistance in HCC.

Multimodal Imaging-Guided Photoimmunotherapy of Pancreatic Cancer by Organosilica Nanomedicine.

Immune checkpoint blockade (ICB) treatments have contributed to substantial clinical progress. However, challenges persist, including inefficient drug delivery and penetration into deep tumor areas, inadequate response to ICB treatments, and potential risk of inflammation due to over-activation of immune cells and uncontrolled release of cytokines following immunotherapy. In response, this study, for the first time, presents a multimodal imaging-guided organosilica nanomedicine (DCCGP) for photoimmunotherapy of pancreatic cancer. The novel DCCGP nanoplatform integrates fluorescence, magnetic resonance, and real-time infrared photothermal imaging, thereby enhancing diagnostic precision and treatment efficacy for pancreatic cancer. In addition, the incorporated copper sulfide nanoparticles (CuS NPs) lead to improved tumor penetration and provide external regulation of immunotherapy via photothermal stimulation. The synergistic immunotherapy effect is realized through the photothermal behavior of CuS NPs, inducing immunogenic cell death and relieving the immunosuppressive tumor microenvironment. Coupling photothermal stimulation with αPD-L1-induced ICB, the platform amplifies the clearance efficiency of tumor cells, achieving an optimized synergistic photoimmunotherapy effect. This study offers a promising strategy for the clinical application of ICB-based combined immunotherapy and presents valuable insights for applications of organosilica in precise tumor immunotherapy and theranostics.

Boosting Checkpoint Immunotherapy with Biomimetic Nanodrug Delivery Systems.

Immune checkpoint blockade (ICB) has achieved unprecedented progress in tumor immunotherapy by blocking specific immune checkpoint molecules. However, the high biodistribution of the drug prevents it from specifically targeting tumor tissues, leading to immune-related adverse events. Biomimetic nanodrug delivery systems (BNDSs) readily applicable to ICB therapy have been widely developed at the preclinical stage to avoid immune-related adverse events. By exploiting or mimicking complex biological structures, the constructed BNDS as a novel drug delivery system has good biocompatibility and certain tumor-targeting properties. Herein, the latest findings regarding the aforementioned therapies associated with ICB therapy are highlighted. Simultaneously, prospective bioinspired engineering strategies can be designed to overcome the four-level barriers to drug entry into lesion sites. In future clinical translation, BNDS-based ICB combination therapy represents a promising avenue for cancer treatment.

Nano-Delivery of Immunogenic Cell Death Inducers and Immune Checkpoint Blockade Agents: Single-Nanostructure Strategies for Enhancing Immunotherapy.

Cancer immunotherapy has revolutionized oncology by harnessing the patient's immune system to target and eliminate cancer cells. However, immune checkpoint blockades (ICBs) face limitations such as low response rates, particularly in immunologically 'cold' tumors. Enhancing tumor immunogenicity through immunogenic cell death (ICD) inducers and advanced drug delivery systems represents a promising solution. This review discusses the development and application of various nanocarriers, including polymeric nanoparticles, liposomes, peptide-based nanoparticles, and inorganic nanoparticles, designed to deliver ICD inducers and ICBs effectively. These nanocarriers improve therapeutic outcomes by converting cold tumors into hot tumors, thus enhancing immune responses and reducing systemic toxicity. By focusing on single-nanoparticle systems that co-deliver both ICD inducers and ICBs, this review highlights their potential in achieving higher drug concentrations at tumor sites, improving pharmacokinetics and pharmacodynamics, and facilitating clinical translation. Future research should aim to optimize these nanocarrier systems for better in vivo performance and clinical applications, ultimately advancing cancer immunotherapy.

Genetically Engineering Cell Membrane-Coated BTO Nanoparticles for MMP2-Activated Piezocatalysis-Immunotherapy.

Tumor immunotherapy based on immune checkpoint blockade (ICB) still suffers from low host response rate and non-specific distribution of immune checkpoint inhibitors, greatly compromising the therapeutic efficiency. Herein, cellular membrane stably expressing matrix metallopeptidase 2 (MMP2)-activated PD-L1 blockades is engineered to coat ultrasmall barium titanate (BTO) nanoparticle for overcoming the immunosuppressive microenvironment of tumors. The resulting M@BTO NPs can significantly promote the BTO's tumor accumulation, while the masking domains on membrane PD-L1 antibodies are cleaved when exposure to MMP2 highly expressed in tumor. With ultrasound (US) irradiation, M@BTO NPs can simultaneously generate reactive oxygen species (ROS) and O2 based on BTO mediated piezocatalysis and water splitting, significantly promoting the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and improving the PD-L1 blockade therapy to the tumor, resulting in effective tumor growth inhibition and lung metastasis suppression in a melanoma mouse model. This nanoplatform combines MMP2-activated genetic editing cell membrane with US responsive BTO for both immune stimulation and specific PD-L1 inhibition, providing a safe and robust strategy in enhancing immune response against tumor.

MTHFR act as a potential cancer biomarker in immune checkpoints blockades, heterogeneity, tumor microenvironment and immune infiltration.

PURPOSE: To evaluate the role and landscape of 5-10-Methylenetetrahydrofolate reductase (MTHFR) to immune infiltration, tumor microenvironment, heterogeneity, immune checkpoints blockades, prognostic significance across cancer types. METHODS: Data sets of genomic, transcriptomic and clinic features of MTHFR across > 60,000 patients and up to 44 cancer types were comprehensively analyzed using R software. RESULTS: Expression of MTHFR gene is significantly lower in 17 tumors and correlated with overall survival (OS), disease-specific survival (DSS), progression-free interval (PFI) in specific tumors. Gene alterations of MTHFR are observed significant differences across tumor types. Expression of MTHFR is negatively correlated with the stemness index (mDNAsi, mRNAsi, DMPsi, ENHsi, EREG-mDNAsi and EREG-mRNAsi) in the most cancers. MTHFR showed significantly correlated with 67 types of immune cell infiltration scores in 44 cancer types by XCELL algorithm. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis are conducted to show the core tumor mechanism and biological process. Correlations between MTHFR and biomarkers of heterogeneity (MSI, TMB, MATH, HRD, LOH, Neoantigen, ploidy and purity) are also significant in specific tumors. MTHFR is significantly positively correlated with biomarkers of immune related genes (CD19, CD274, CD80, CD86) and mismatched repair genes (MLH1, PMS2, MSH2, MSH6, EPCAM, MLH3, PMS1, EXO1) in most cancer types. Receiver Operating Characteristics (ROC) analyses show MTHFR could act as a potential biomarker in anti-PD-1 (nivolumab to melanoma) and anti-CTLA4 (ipilimumab to melanoma) group of ontreatment, in anti-PD-1 (pembrolizumab to melanoma) group of pretreatment. Two immunohistochemistry antibodies HPA076180 and HPA077255 are verified in 20 types of tumor and could be used to detect the expression of MTHFR efficiently in clinic. CONCLUSIONS: MTHFR could predict the response of immune checkpoints blockades, heterogeneity, tumor microenvironment and immune infiltration.

Tumor Cell-Responsive Photodynamic Immunoagent for Immunogenicity-Enhanced Orthotopic and Remote Tumor Therapy.

Combining photodynamic therapy (PDT) and immune checkpoint blockades is an efficient method to maximize immunotherapeutic outcome by boosting tumor immunogenicity and modulating the immunosuppressive tumor microenvironment. However, the always-on bioactivity of photosensitizers or immune checkpoint inhibitors leads to uncontrollable side effects, limiting the in vivo therapeutic efficacy of treatments. An activatable strategy is of great importance for improving the selectivity during cancer therapy. In this study, a photodynamic immunomodulator, ICy-NLG, is developed by conjugating the photosensitizer ICy-NH2 with the indoleamine 2,3-dioxygenase 1 inhibitor NLG919 through a glutathione (GSH)-cleavable linker to achieve activatable photodynamic immunotherapy. The conjugation considerably suppresses both the PDT effect and the activity of the inhibitor. After ICy-NLG is activated by high levels of GSH in tumor cells, the PDT effect is restored and leads to immunogenic tumor cell death. The released tumor-associated antigens in conjunction with the activated immune checkpoint inhibitor induce a synergistic antitumor immune response, resulting in the growth inhibition of primary and distant tumors and the prevention of lung metastasis in mouse xenograft models.

Immunotherapeutic approaches in Hepatocellular carcinoma: Building blocks of hope in near future.

Hepatocellular carcinoma (HCC) is the most common type of primary hepatic cancer and is among the major causes of mortality due to cancer. Due to the lack of efficient conventional therapeutic options for this cancer, particularly in advanced cases, novel treatments including immunotherapy have been considered. However, despite the encouraging clinical outcomes after implementing these innovative approaches, such as oncolytic viruses (OVs), adoptive cell therapies (ACT), immune checkpoint blockades (ICBs), and cancer vaccines, several factors have restricted their therapeutic effect. The main concern is the existence of an immunosuppressive tumor microenvironment (TME). Combination of different ICBs or ICBs plus tyrosine kinase inhibitors have shown promising results in overcoming these limiting factors to some extent. Combination of programmed cell death ligand-1 (PD-L1) antibody Atezolizumab and vascular endothelial growth factor (VEGF) antibody Bevacizumab has become the standard of care in the first-line therapy for untestable HCC, approved by regulatory agencies. This paper highlighted a wide overview of the direct and indirect immunotherapeutic strategies proposed for the treatment of HCC patients and the common challenges that have hindered their further clinical applications.

Cancer Stem Cells and Anti-tumor Immunity.

Cancer stem cells (CSCs) are correlated with poor clinical outcomes due to their contribution to chemotherapy resistance and the formation of metastasis. Multiple cell surface and enzymatic markers have been characterized to identify CSCs, which is important for diagnosis, therapy, and prognosis. This review underlines the role of CSCs and circulating tumor cells (CTCs) in tumor relapse and metastasis, the characteristics of CSC and CTC biomarkers, and the techniques used to detect these cells. We also summarized novel therapeutic approaches toward targeting CSCs, especially focusing on the role of immune checkpoint blockades (ICB), such as anti-programmed death 1 (anti-PD1) and antiprogrammed death ligand-1 (anti-PDL1) therapies. Additionally, we address an intriguing new mechanism of action for small molecular drugs, such as telomere-targeted therapy 6-thio-2'deoxyguanosine (6- thio-dG), and how it reshapes tumor microenvironment to overcome ICB resistance. There are indications, that personalized cancer therapy targeting CSC populations in conjunction with immune-mediated strategy hold promise for the removal of residual therapy-resistant CSCs in the near future.

Polarization of Cancer-Associated Macrophages Maneuver Neoplastic Attributes of Pancreatic Ductal Adenocarcinoma.

Mounting evidence links the phenomenon of enhanced recruitment of tumor-associated macrophages towards cancer bulks to neoplastic growth, invasion, metastasis, immune escape, matrix remodeling, and therapeutic resistance. In the context of cancer progression, naïve macrophages are polarized into M1 or M2 subtypes according to their differentiation status, gene signatures, and functional roles. While the former render proinflammatory and anticancer effects, the latter subpopulation elicits an opposite impact on pancreatic ductal adenocarcinoma. M2 macrophages have gained increasing attention as they are largely responsible for molding an immune-suppressive landscape. Through positive feedback circuits involving a paracrine manner, M2 macrophages can be amplified by and synergized with neighboring neoplastic cells, fibroblasts, endothelial cells, and non-cell autonomous constituents in the microenvironmental niche to promote an advanced disease state. This review delineates the molecular cues expanding M2 populations that subsequently convey notorious clinical outcomes. Future therapeutic regimens shall comprise protocols attempting to abolish environmental niches favoring M2 polarization; weaken cancer growth typically assisted by M2; promote the recruitment of tumoricidal CD8+ T lymphocytes and dendritic cells; and boost susceptibility towards gemcitabine as well as other chemotherapeutic agents.

Chrysin inhibits hepatocellular carcinoma progression through suppressing programmed death ligand 1 expression.

BACKGROUNDS: The aberrant PD-L1 expression on cancer cells was confirmed to participate in immune evasion of hepatocellular carcinoma (HCC). Previous studies had documented that there were anti-tumorigenic effects of chrysin on HCC. However, whether chrysin can act on the over-expressed PD-L1 on HCC cells to exert the therapeutic effectiveness and the involved mechanisms has not yet been deciphered. PURPOSE: Herein, we aimed to explore the regulatory effects of chrysin on the PD-1/PD-L1 immune checkpoint and investigate its possible mechanisms in vivo and in vitro. METHODS: H22 xenograft mouse model was used to investigate the effects of chrysin on tumor growth and PD-L1 expression in tumors. In interferon-gamma (IFN-γ)-induced HepG2 cells, the cytotoxicity of chrysin was detected by MTT assay. Flow cytometry, ELISA and RT-PCR were carried out to evaluate the expression of PD-L1, and the expression of proteins in STAT3 and NF-κB pathways was also determined by Western blot. In HepG2 cells and Jurkat T cell co-culture system, ELISA kit was used to detect the level of IL-2, and T cell proliferation was further evaluated by CCK-8 method. RESULTS: Our data suggested that chrysin could effectively inhibit the progression of tumor, and promote the anti-tumor immunity of mice concomitant with enhanced CD4/CD8-positive T cell proportion in tumor tissues of H22 xenograft mouse model. Additionally, chrysin significantly down-regulated the expression of PD-L1 in vivo and in vitro, which was closely associated with the blockage of STAT3 and NF-κB pathways. Moreover, in the co-culture system, chrysin could increase the proliferation of T cells and the concentration of IL-2. CONCLUSION: These results indicate that chrysin may have the potential to be an immune checkpoint inhibitor for preventive or as an adjunctive curative agent for HCC.

Identification of a Novel Epithelial-Mesenchymal Transition-Related Gene Signature for Endometrial Carcinoma Prognosis.

(1) Background: Endometrial cancer is the most prevalent cause of gynecological malignant tumor worldwide. The prognosis of endometrial carcinoma patients with distant metastasis is poor. (2) Method: The RNA-Seq expression profile and corresponding clinical data were downloaded from the Cancer Genome Atlas database and the Gene Expression Omnibus databases. To predict patients' overall survival, a 9 EMT-related genes prognosis risk model was built by machine learning algorithm and multivariate Cox regression. Expressions of nine genes were verified by RT-qPCR. Responses to immune checkpoint blockades therapy and drug sensitivity were separately evaluated in different group of patients with the risk model. (3) Endometrial carcinoma patients were assigned to the high- and low-risk groups according to the signature, and poorer overall survival and disease-free survival were showed in the high-risk group. This EMT-related gene signature was also significantly correlated with tumor purity and immune cell infiltration. In addition, eight chemical compounds, which may benefit the high-risk group, were screened out. (4) Conclusions: We identified a novel EMT-related gene signature for predicting the prognosis of EC patients. Our findings provide potential therapeutic targets and compounds for personalized treatment. This may facilitate decision making during endometrial carcinoma treatment.

Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021.

The United States Food and Drug Administration (US FDA) has always been a forerunner in drug evaluation and supervision. Over the past 31 years, 1050 drugs (excluding vaccines, cell-based therapies, and gene therapy products) have been approved as new molecular entities (NMEs) or biologics license applications (BLAs). A total of 228 of these 1050 drugs were identified as cancer therapeutics or cancer-related drugs, and 120 of them were classified as therapeutic drugs for solid tumors according to their initial indications. These drugs have evolved from small molecules with broad-spectrum antitumor properties in the early stage to monoclonal antibodies (mAbs) and antibody‒drug conjugates (ADCs) with a more precise targeting effect during the most recent decade. These drugs have extended indications for other malignancies, constituting a cancer treatment system for monotherapy or combined therapy. However, the available targets are still mainly limited to receptor tyrosine kinases (RTKs), restricting the development of antitumor drugs. In this review, these 120 drugs are summarized and classified according to the initial indications, characteristics, or functions. Additionally, RTK-targeted therapies and immune checkpoint-based immunotherapies are also discussed. Our analysis of existing challenges and potential opportunities in drug development may advance solid tumor treatment in the future.

In Situ Crosslinked Hydrogel Depot for Sustained Antibody Release Improves Immune Checkpoint Blockade Cancer Immunotherapy.

The therapeutic inhibition of immune checkpoints, including cytotoxic T lymphocyte-associated protein (CTLA)-4 and programmed cell death 1 (PD-1), through the use of function blocking antibodies can confer improved clinical outcomes by invigorating CD8+ T cell-mediated anticancer immunity. However, low rates of patient responses and the high rate of immune-related adverse events remain significant challenges to broadening the benefit of this therapeutic class, termed immune checkpoint blockade (ICB). To overcome these significant limitations, controlled delivery and release strategies offer unique advantages relevant to this therapeutic class, which is typically administered systemically (e.g., intravenously), but more recently, has been shown to be highly efficacious using locoregional routes of administration. As such, in this paper, we describe an in situ crosslinked hydrogel for the sustained release of antibodies blocking CTLA-4 and PD-1 signaling from a locoregional injection proximal to the tumor site. This formulation results in efficient and durable anticancer effects with a reduced systemic toxicity compared to the bolus delivery of free antibody using an equivalent injection route. This formulation and strategy thus represent an approach for achieving the efficient and safe delivery of antibodies for ICB cancer immunotherapy.

Clinical outcomes of immune checkpoint blockades and the underlying immune escape mechanisms in squamous and adenocarcinoma NSCLC.

Immune checkpoint blockades (ICBs) have changed the standard of care of squamous and adenocarcinoma non-small cell lung cancer (NSCLC). Whereas detailed researches regarding ICBs in the two major histological subtypes are rare. In order to uncover the clinical efficacy differences between squamous and adenocarcinoma NSCLC and better understand the underlying immune-regulatory mechanisms, we compared the survival benefits of ICBs between the two subtypes by revealing phase 3 randomized trials and attempted to uncover the immune-regulatory discrepancy. Generally, compared with nonsquamous NSCLC, squamous NSCLC benefited more from ICBs in Keynote 024, CheckMate 026, CheckMate 227 and CheckMate 017 and similar in OAK, but less in Keynote 010 and PACIFIC. We revealed that the tumor mutation burden (TMB) level, the programmed cell death ligand 1 (PD-L1) expression, tumor infiltrating lymphocytes (TILs) in the tumor microenvironment (TME), chemokines, and oncogenic driver alterations within the two subtypes may contributed to the clinical outcomes of ICBs. We prospected that the combinations of ICBs with chemotherapy, radiation therapy, and antiangiogenic therapy could be promising strategies to re-immunize the less immunogenic tumors and further enhance the efficacy of ICBs.