Stimulating a robust cancer-immunity cycle (CIC) holds promising potential for eliciting potent and enduring immune responses for cancer immunotherapy. However, designing a therapeutic nanomaterial capable of both enhancing tumor immunogenicity and mitigating immunosuppression is challenging and often associated with complicated design paradigms and immune-related adverse effects. Herein, a multienzyme-mimetic alloy nanosheet incorporating palladium (Pd) and iron (Fe) is developed, which can prime effective CIC by overcoming ferroptosis resistance for enhancing tumor immunogenicity and reprograming the tumor microenvironment for enhanced second near-infrared (NIR-II) photoimmunotherapy. The nanosheets accumulate in tumors when administered intravenously and counteract hypoxia through catalase-like oxygen production and subsequent reduction of hypoxia-inducible factor-1α, M2-like macrophages, regulatory T-cell, and programmed death-ligand 1 (PD-L1) expression. The surface plasmon resonance of the nanosheets enables NIR-II phototherapy and photoacoustic imaging, coupling with its ferroptosis and tumor microenvironment reprogram properties to synergize with anti-PD-L1 checkpoint blockade therapy to achieve satisfactory antitumor outcome. This study offers a strategy for localized tumor treatment and boosting the CIC through a straightforward and inexpensive nanomaterial design.

Immune checkpoint blockade (ICB) therapy is a widely favored anti-tumor treatment, but it shows limited response to non-immunogenic "cold" tumors and suffers from drug resistance. Photodynamic therapy (PDT), as a powerful localized treatment approach, can convert a "cold tumor" into a "hot tumor" by inducing immunogenic cell death (ICD) in tumor cells, thereby enhancing tumor immunogenicity and promoting tumor immunotherapy. However, the effectiveness of PDT is largely hindered by the limited penetration depth into tumor tissues. To address these issues, we proposed an all-in-one drug system with NIR-II photo-accelerated PDT effects, efficient immune checkpoint gene silencing, and a facile manufacturing process. The so-called all-in-one drug system comprises a multi-modal designed polymer PPNP and siRNA. PPNP is an amphipathic polymer that includes the near infrared-II (NIR-II) photosensitizer Aza-boron-dipyrromethene (Aza-BODIPY), a glutathione (GSH)-cleavable linker, and a cationic monomer derived from cholesterol. PPNP can self-assemble and efficiently load siRNA. Under laser irradiation, PPNP triggers a potent ICD cascade, causing the on-demand release of siPD-L1, reshaping the tumor's immunosuppressive microenvironment, effectively inhibiting the growth of various tumors, and stimulating the immune memory. This study represents a generalized platform for PDT and gene silencing, designed to modulate immune-related signaling pathways for improved anticancer therapy.

The successful approval of peptide-based drugs can be attributed to a collaborative effort across multiple disciplines. The integration of novel drug design and synthesis techniques, display library technology, delivery systems, bioengineering advancements, and artificial intelligence have significantly expedited the development of groundbreaking peptide-based drugs, effectively addressing the obstacles associated with their character, such as the rapid clearance and degradation, necessitating subcutaneous injection leading to increasing patient discomfort, and ultimately advancing translational research efforts. Peptides are presently employed in the management and diagnosis of a diverse array of medical conditions, such as diabetes mellitus, weight loss, oncology, and rare diseases, and are additionally garnering interest in facilitating targeted drug delivery platforms and the advancement of peptide-based vaccines. This paper provides an overview of the present market and clinical trial progress of peptide-based therapeutics, delivery platforms, and vaccines. It examines the key areas of research in peptide-based drug development through a literature analysis and emphasizes the structural modification principles of peptide-based drugs, as well as the recent advancements in screening, design, and delivery technologies. The accelerated advancement in the development of novel peptide-based therapeutics, including peptide-drug complexes, new peptide-based vaccines, and innovative peptide-based diagnostic reagents, has the potential to promote the era of precise customization of disease therapeutic schedule.

Recently identified palmitoylation of PD-L1 is essential for immune regulation. To elucidate the underlying molecular mechanism, we performed giant plasma membrane vesicle (GPMV) experiments, μs-scale all-atom molecular dynamics (MD) simulations, fluorescence resonance energy transfer (FRET) experiments, and immune killing experiments. GPMV experiments indicated that PD-L1 palmitoylation enhanced its lipid raft affinity. MD simulations revealed dramatically different membrane orientation states of PD-L1 in liquid-ordered (Lo, lipid raft) compared to liquid-disordered (Ld, nonraft) membrane environments, which was validated by FRET experiments. The Ld region promoted the "lie-down" orientation of PD-L1, which could inhibit its association with the PD-1 protein on immune cells and thus promote the immune killing of cancer cells. This hypothesis was supported by immune killing experiments using γδT cells as effector cells and NCI-H1299 lung cancer cells as target cells. In short, our study demonstrates that the palmitoylation affects PD-L1's membrane localization and then membrane orientation, which thus regulates its binding with T cell PD-1 and the immune regulation. These observations may guide therapeutic strategies by explicating the regulation of immune checkpoint proteins by post-translational modifications and membrane environments.

Advancing at the cutting edge of oncology, the synergistic application of photothermal therapy coupled with immunotherapy is rapidly establishing itself as an innovative and potent strategy against cancer. A critical challenge in this domain is the precise and efficient targeting of tumor tissues with photothermal agents and immunoadjuvants while minimizing interference with healthy tissues. In this paper, we introduce an ingenious biomimetic nanoparticle platform, cancer cell membrane coated F127/(R837 and IR1048) (CFRI) nanoparticles encapsulating a near-infrared region II photothermal agent, IR1048, and an immunostimulatory molecule, R837, with their surface modified using membranes derived from tumor cells, conferring exceptional specificity for tumor targeting. CFRI nanoparticles demonstrated an extraordinary photothermal conversion efficiency of 49%, adeptly eradicating in situ tumors. This process also triggered the release of damage-associated molecular patterns, thereby activating dendritic cells and catalyzing the maturation and differentiation of T cells, initiating a robust immune response. In vivo animal models substantiated that the CFRI-mediated synergistic photothermal and immunotherapeutic strategy markedly suppressed the proliferation of in situ tumors and provoked a vigorous systemic immune response, effectively curtailing the metastasis and recurrence of distant tumors. The successful development of the CFRI nanoparticle system offers a promising horizon for future clinical translations and pioneering research in oncology.

Immunotherapy holds notable progress in the treatment of cancer. However, the clinical therapeutic effect remains a significant challenge due to immune-related side effects, poor immunogenicity, and immunosuppressive microenvironment. Nanoparticles have emerged as a revolutionary tool to surmount these obstacles and amplify the potency of immunotherapeutic agents. Prussian blue nanoparticles (PBNPs) exhibit multi-dimensional immune function in cancer immunotherapy, including acting as a nanocarrier to deliver immunotherapeutic agents, as a photothermal agent to improve the efficacy of immunotherapy through photothermal therapy, as a nanozyme to regulate tumor microenvironment, and as an iron donor to induce immune events related to ferroptosis and tumor-associated macrophages polarization. This review focuses on the advances and applications of PBNPs in cancer immunotherapy. First, the biomedical functions of PBNPs are introduced. Then, based on the immune function of PBNPs, we systematically reviewed the multidimensional application of PBNPs in cancer immunotherapy. Finally, the challenges and future developments of PBNPs-based cancer immunotherapy are highlighted.

Cell-based immunotherapy has revolutionized cancer treatment in recent years and is rapidly expanding as one of the major therapeutic options in immuno-oncology. So far ten adoptive T cell therapies (TCTs) have been approved by the health authorities for cancer treatment, and they have shown remarkable anti-tumor efficacy with potent and durable responses. While adoptive T cell therapies have shown success in treating hematological malignancies, they are lagging behind in establishing promising efficacy in treating solid tumors, partially due to our incomplete understanding of the cellular kinetics (CK) and biodistribution (including tumoral penetration) of cell therapy products. Indeed, recent clinical studies have provided ample evidence that CK of TCTs can influence clinical outcomes in both hematological malignancies and solid tumors. In this review, we will discuss the current knowledge on the CK and biodistribution of anti-tumor TCTs. We will first describe the typical CK and biodistribution characteristics of these "living" drugs, and the biological factors that influence these characteristics. We will then review the relationships between CK and pharmacological responses of TCT, and potential strategies in enhancing the persistence and tumoral penetration of TCTs in the clinic. Finally, we will also summarize bioanalytical methods, preclinical in vitro and in vivo tools, and in silico modeling approaches used to assess the CK and biodistribution of TCTs.

Cervical cancer is preventable with screening and vaccination approaches; however, access to these preventative measures is limited both nationally and globally and thus many women will still develop cervical cancer. Novel treatments and practice-changing research have improved cervical cancer outcomes over the past few decades. In this Review, we discuss clinical trials that have refined or redefined the treatment of cervical cancers across the early stage, locally advanced, persistent, recurrent and/or metastatic disease settings. Advances for patients with early stage disease have been achieved through trials evaluating less extensive and fertility-preserving surgeries, different surgical approaches (open versus minimally invasive), and sentinel versus full pelvic lymph node dissection. We also discuss results from trials testing the use of neoadjuvant, induction and adjuvant chemotherapy as well as immune-checkpoint inhibitors in patients with locally advanced disease. Finally, we review the progress made with systemic chemotherapy and novel therapeutics, including anti-angiogenic agents, immune-checkpoint inhibitors and antibody-drug conjugates, in the setting of metastatic and/or recurrent cervical cancer. The advances highlighted in this manuscript have reduced morbidity and improved overall survival for patients with this challenging-to-treat disease, while also inspiring additional research and trials in the field.

Convincing evidence revealed that some platinum-based drugs could stimulate immunological recognition, thereby inducing immunogenic cell death (ICD). Indoleamine-2,3-dioxygenase (IDO) is overexpressed in tumors, which caused exhaustion of tryptophan (T-cell energy) and constructed an immunosuppressive tumor microenvironment. Herein, considering IDO inhibition to improve chemotherapy, a series of IDOi-Pt(IV) prodrugs were designed to not only target DNA and IDO but also facilitate tumor-antigen exposure and immunomodulation. The optimal IDOi-Pt(IV) prodrugs (named compound 10) significantly enhanced intracellular accumulation 22.4-fold and cytotoxicity 61.75-fold superior to cisplatin in HeLa cells. Moreover, immunofluorescence and enzyme-linked immunosorbent assays revealed that 10 induced reactive oxygen species-mediated endoplasmic reticulum stress and secretion of damage-associated molecular patterns, thereby presenting ICD effects. Molecular docking, enzyme inhibition, and Western blot assays demonstrated that 10 could effectively inhibit IDO1 and reverse immunosuppression, as further verified by mixed leukocyte reactions. In vivo tests showed that 10 exhibited high-efficiency and low-toxicity antitumor effects compared to cisplatin, presenting successful chemoimmunotherapy.

As one part of the innate immune response to external stimuli, chronic inflammation increases the risk of various cancers, and tumor-promoting inflammation is considered one of the enabling characteristics of cancer development. Recently, there has been growing evidence on the role of anti-inflammation therapy in cancer prevention and treatment. And researchers have already achieved several noteworthy outcomes. In the review, we explored the underlying mechanisms by which inflammation affects the occurrence and development of cancer. The pro- or anti-tumor effects of these inflammatory factors such as interleukin, interferon, chemokine, inflammasome, and extracellular matrix are discussed. Since FDA-approved anti-inflammation drugs like aspirin show obvious anti-tumor effects, these drugs have unique advantages due to their relatively fewer side effects with long-term use compared to chemotherapy drugs. The characteristics make them promising candidates for cancer chemoprevention. Overall, this review discusses the role of these inflammatory molecules in carcinogenesis of cancer and new inflammation molecules-directed therapeutic opportunities, ranging from cytokine inhibitors/agonists, inflammasome inhibitors, some inhibitors that have already been or are expected to be applied in clinical practice, as well as recent discoveries of the anti-tumor effect of non-steroidal anti-inflammatory drugs and steroidal anti-inflammatory drugs. The advantages and disadvantages of their application in cancer chemoprevention are also discussed.

Analyzing the cell interface is of paramount importance in understanding how cells interact and communicate with other cells, but an advanced analytical platform that can process complex and networked interactions between cell surface ligands and receptors is lacking. Herein, we developed the cell-interface-deciphering lipid nanotablet (CID-LNT) for multiplexed real-time cell analysis. LNT is a nanoparticle-tethered lipid bilayer chip where freely diffusing plasmonic nanoparticles induce scattering signal changes. The CID-LNT transduces cell surface protein information into DNA data, which operate as nanoparticle logic gates. As a proof of concept, we detected and analyzed programmed death-ligand 1 (PD-L1) and associated immune signals (TNF-α, EGF, and IFN-γ). PD-L1 is an immune checkpoint that suppresses T cell activity with inflammatory biomolecules facilitating its expression. The CID-LNT can serve as a dynamic nanoparticle logic board, enabling the logic gate-based analysis of membrane proteins, and can be expanded to immunological synapse analysis, cell interface engineering, and molecular diagnostics.

Racial differences in antitumoral immunity have been identified in a variety of cancers and may contribute to survival disparities, but limited data exist exploring the molecular differences in pancreatic adenocarcinoma (PDAC). Using racially diverse PDAC datasets, we explored biologic differences that may drive disparities between African American (AA) and European American (EA) PDAC patients.

Genomic PDAC mutational data was analyzed for mutational differences based on race. In a separate cohort, surgical PDAC specimens were processed for both tissue microarray and multiplex gene expression analysis using NanoString.

Of the 4679 patient samples in the mutational dataset, AA PDAC patients had significantly more TP53 mutations compared to the EA cohort. The tissue microarray included 12 AA and 41 EA surgically resected treatment-naive PDAC samples. NanoString analysis revealed significant differences between AA and EA groups in immunologic gene annotations (P < 0.05).

In the present study, we demonstrated that across racially diverse datasets, there exist molecular and microenvironmental differences between AA and EA patients that may contribute to cancer survival disparities. Defining molecular differences underlying PDAC racial disparities is an essential step in advancing care and improving outcomes for AA patients that suffer worse survival across cancer types.

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment. However, the outcomes of mainstay antibody inhibitors against solid tumors remain poor, facing tremendous challenges including manufacturing complexities, serious toxicities, and crosstalk among multiple checkpoints. Herein, we present a bispecific molecularly imprinted nanoimmunoblocker (bsMINIB) designed to boost potent antitumor immunity via synchronously blocking innate and adaptive immune checkpoints. Two epitopes for PD-L1 and SIRPα are selected as templates through structural analysis, and thereafter, bsMINIB capable of bridging tumor cells and macrophages is rationally engineered via an advanced imprinting approach. The bsMINIB exhibits high affinity and specificity toward PD-L1 on solid tumor cells and SIRPα on macrophages, allowing effective disruption of both PD-L1/PD-1 and CD47/SIRPα signaling. These signal disruptions restore macrophage-mediated tumor phagocytosis, promote tumor-associated antigen presentation, and reinvigorate T cell-mediated tumor killing. Using refractory triple-negative breast cancer as a solid tumor model, the bsMINIB demonstrates extended retention at the tumor site, amplified infiltration of active T cells, and reactivated antitumor macrophages, thereby effectively inhibiting tumor growth. This biomimetic nanoimmunoblocker not only presents an effective multipronged ICB therapeutic against solid tumors but also showcases a compelling paradigm for the rational engineering of bispecific nanoplatforms for synergistic immunotherapy through molecular imprinting.

The perioperative period is crucial for determining postoperative tumor recurrence and metastasis. Various factors in postoperative lesions can diminish the therapeutic effect of conventional chemoradiotherapy, while emerging immunotherapy is restricted. The combination use of inflammatory inhibitors during treatment is also controversial. Here, a modular microneedle prepared from engineered keratin proteins is reported, which spatially and temporally differentiates the microenvironment of immune cell activation required for immunotherapy from that of wound healing. The recombinant keratin-84-T-based needle root layer, mainly retained in the epidermis, facilitated dendritic cell recruitment to achieve maximum antigen presentation of loaded vaccines. Meanwhile, the recombinant keratin-81-1Aα-based needle tip layer, located within the dermis, rapidly mitigated inflammatory responses while promoting tissue repair and regeneration. Unlike simply mixing immunotherapy and wound treatment, this spatiotemporal segmentation approach maximized the efficacy of immune therapeutics while promoting wound healing, making it suitable for application throughout the perioperative period.

The pivotal role of type 1 conventional dendritic cells (cDC1s) in the field of dendritic cell (DC)-based tumor immunotherapies has been gaining increasing recognition due to their superior antigen cross-presentation abilities and essential role in modulating immune responses. This review specifically highlights the C-type lectin receptor family 9 member A (Clec9a or DNGR-1), which is exclusively expressed on cDC1s and plays a pivotal role in augmenting antigen cross-presentation and cytotoxic T lymphocyte (CTL) responses while simultaneously mitigating off-target effects. These effects include the enhancement of the cDC1s cross-presentation, reducing autoimmune responses and systemic inflammation, as well as preventing the non-specific activation of other immune cells. Consequently, these actions may contribute to reduced toxicity and enhanced treatment efficacy in immunotherapy. The exceptional ability of Clec9a to cross-present dead cell-associated antigens and enhance both humoral and CTL responses makes it an optimal receptor for DC-based strategies aimed at strengthening antitumor immunity. This review provides a comprehensive overview of the molecular characterization, expression, and signaling mechanisms of Clec9a. Furthermore, it discusses the role of Clec9a in the induction and functional activation of Clec9a+ cDC1s, with a particular focus on addressing the challenges related to off-target effects and immune tolerance in the development of tumor vaccines. Additionally, this review explores the potential of Clec9a-targeted approaches to enhance the immunogenicity of tumor vaccines and addresses the utilization of Clec9a as a delivery target for specific agonists (such as STING agonists and αGC) to enhance their therapeutic effects. This novel approach leverages Clec9a's capacity to improve the precision and efficacy of these immunomodulatory molecules in tumor treatment. In summary, this review presents compelling evidence positioning Clec9a as a promising target for DC-based tumor immunotherapy, capable of enhancing the efficacy of vaccines and immune responses while minimizing adverse effects.

We examine the complex relationship between genomic copy number variation (CNV) and gene expression, highlighting the relevance to cancer biology and other biological contexts. By tracing the history of genometranscriptome correlations, we emphasize the complexity and challenges in understanding these interactions, particularly within the heterogeneous landscape of human cancers. Recent advances in computational algorithms and high-throughput single-cell multi-omic sequencing technologies are discussed, demonstrating their potential to refine our understanding of cancer biology and their limitations. The integration of genomic and transcriptomic analyses, which offers novel insights into tumor evolution and heterogeneity as well as therapeutic strategies, is presented as a crucial approach for advancing cancer research.

Inadequate antigen capture and insufficient antigen-presenting cell (APC) activity at tumor sites limit the effectiveness of in situ vaccines. To address this, poly(glutamic acid-cholinephosphate) (pGluCP) is introduced as a polymer with cell membrane adhesion properties capable of capturing both water-soluble and insoluble membrane antigens from necrotic tumor cells while recruiting more APCs. The approach uses manganese-mineralized black phosphorus (MnBP) coated with pGluCP and αPD-1 antibodies to create the MnBP@pGluCP-αPD-1 complex for in situ vaccines. MnBP eradicates tumor cells via photothermal effects, releasing antigens, while Mn2⁺ ions activate the intracellular STING pathway, acting as an adjuvant. pGluCP captures these antigens, forming pathogen-mimicking micro-nanoparticles, leading to an in situ vaccine (MnBP@pGluCP/antigens) that co-localizes antigens and adjuvants. The αPD-1 antibody alleviates tumor-induced immune suppression, enhancing tumor cell-specific killing. This study demonstrates the potential of leveraging cholinephosphate-cell membrane interactions to improve antigen presentation efficiency, significantly bolstering the efficacy of in situ tumor vaccines and opening new avenues for advanced cancer immunotherapy.

A major advance in cancer treatment has been the development and refinement of cancer immunotherapy. The discovery of immunotherapies for a wide range of cancers has revolutionized cancer treatment paradigms. Despite relapse or refractory disease, immunotherapy approaches can prolong the life expectancy of metastatic cancer patients. Multiple therapeutic approaches and agents are currently being developed to manipulate various aspects of the immune system. Oncolytic viruses, cancer vaccines, adoptive cell therapies, monoclonal antibodies, cytokine therapies, and inhibitors of immune checkpoints have all proven successful in clinical trials. There are several types of immunotherapeutic approaches available for treating cancer, and others are being tested in preclinical and clinical settings. Immunotherapy has proven successful, and many agents and strategies have been developed to improve its effectiveness. The purpose of this article is to present a comprehensive overview of current immunotherapy approaches used to treat cancer. Cancer immunotherapy advancements, emerging patterns, constraints, and potential future breakthroughs are also discussed.

Market bubbles emerge when asset prices are driven unsustainably higher than asset values, and shifts in belief burst them. We demonstrate an analogous phenomenon in the case of biomedical knowledge, when promising research receives inflated attention. We introduce a diffusion index that quantifies whether research areas have been amplified within social and scientific bubbles, or have diffused and become evaluated more broadly. We illustrate the utility of our diffusion approach in tracking the trajectories of cardiac stem cell research (a bubble that collapsed) and cancer immunotherapy (which showed sustained growth). We then trace the diffusion of 28,504 subfields in biomedicine comprising nearly 1.9 M papers and more than 80 M citations to demonstrate that limited diffusion of biomedical knowledge anticipates abrupt decreases in popularity. Our analysis emphasizes that restricted diffusion, implying a socio-epistemic bubble, leads to dramatic collapses in relevance and attention accorded to scientific knowledge.

Bispecific antibodies (BsAbs) represent a promising strategy for cancer immunotherapy. Challenges in immunotherapy include inefficient early events in the immune response cycle, such as antigen presentation and T cell priming. Background stimulation of CD40 with agonistic antibodies is a promising strategy to enhance the therapeutic efficacy of immune checkpoint inhibitors (ICIs). Assisted by Alphafold2(AlphaFold-Multimer), we developed a humanized CD40 agonistic antibody that exhibits activation only in the presence of cross-linking. It also demonstrates that the current AlphaFold2(AlphaFold2-Multimer) can predict antibody-antigen complexes. Due to the unique epitope, it demonstrates superior activation compared to APX005M (S267E). Building upon this, we created a novel bispecific antibody (anti-PD-L1/CD40 bispecific antibody, referred to as "BA4415") designed to activate CD40 signaling specifically in the context of PD-L1 while simultaneously blocking PD-1/PD-L1 signaling. Results from functional evaluations using effector cells revealed the superior biological activity of BA4415 compared to the combination of each monoclonal antibody. BA4415 demonstrated the ability to enhance T-cell cytokine release in vitro assays, exhibiting superior functional attributes compared to the anti-PD-L1 antibody. Furthermore, in humanized transgenic mice challenged with huPD-L1-expressing tumor cells, BA4415 induced superior anti-tumor activity. This novel anti-PD-L1/CD40 bispecific antibody holds potential for strong anti-tumor therapeutic efficacy by selectively restricting CD40 stimulation in tumors.

In alignment with the World Health Organization's strategy to eliminate cervical cancer, substantial progress has been made in the treatment of this malignancy. Cervical cancer, largely driven by human papillomavirus (HPV) infection, is considered preventable and manageable because of its well-established etiology. Advancements in precision screening technologies, such as DNA methylation triage, HPV integration detection, liquid biopsies, and artificial intelligence-assisted diagnostics, have augmented traditional screening methods such as HPV nucleic acid testing and cytology. Therapeutic strategies aimed at eradicating HPV and reversing precancerous lesions have been refined as pivotal measures for disease prevention. The controversy surrounding surgery for early-stage cervical cancer revolves around identifying optimal candidates for minimally invasive and conservative procedures without compromising oncological outcomes. Recent clinical trials have yielded promising results for the development of systemic therapies for advanced cervical cancer. Immunotherapies, such as immune checkpoint inhibitors (ICIs), antibody-drug conjugates (ADCs), and targeted therapy have demonstrated significant effectiveness, marking a substantial advancement in cervical cancer management. Various combination therapies have been validated, and ongoing trials aim to enhance outcomes through the development of novel drugs and optimized combination regimens. The prospect of eradicating cervical cancer as the first malignancy to be eliminated is now within reach. In this review, we provide a comprehensive overview of the latest scientific insights, with a particular focus on precision managements for various stages of cervical disease, and explore future research directions in cervical cancer.

The management and treatment of tumor complications pose continuous challenges due to the inherent complexity. However, the advent of drug delivery systems (DDSs) brings promising opportunities to address the tumor complications using innovative technological approaches. This review focuses on common oncological complications, including cancer thrombosis, malignant serous effusion, tumor-associated infections, cancer pain, and treatment-related complications. Emphasis was placed on the application and potential of DDSs in mitigating and treating these tumor complications, and we delved into the underlying mechanisms of common cancer-associated complications, discussed the limitations of conventional treatments, and outlined the current status and potential development of DDSs for various complications in this review. Moreover, we have discussed the existing challenges in DDSs research, underscoring the need for addressing issues related to biocompatibility and targeting of DDSs, optimizing drug delivery routes, and enhancing delivery efficiency and precision. In conclusion, DDSs offer promising avenues for treating cancer complications, offering the potential for the development of more effective and safer drug delivery strategies, thereby improving the quality of life and survival rates of cancer patients.

Immunotherapy represents an emergent and heterogeneous group of anticancer treatments harnessing the human immune-surveillance system, including immune-checkpoint inhibitor monoclonal antibodies (mAbs), Chimeric Antigen Receptor T Cells (CAR-T) therapy, cancer vaccines and lymphocyte activation gene-3 (LAG-3) therapy. While remarkably effective against several malignancies, these therapies, often in combination with other cancer treatments, have showed unforeseen toxicity, including cardiovascular complications. The occurrence of immuno-mediated adverse (irAEs) events has been progressively reported in the last 10 years. These irAEs present an extended range of severity, from self-limiting to life-threatening conditions. Although recent guidelines in CardioOncology have provided important evidence in managing cancer treatments, they often encompass general approaches. However, a specific focus is required due to the particular etiology, unique risk factors, and associated side effects of immunotherapy. This review aims to deepen the understanding of the prevalence and nature of cardiovascular issues in patients undergoing immunotherapy, offering insights into strategies for risk stratification and management.

The amazing diversity of B cells within the tumor microenvironment is the basis for the diverse development of B cell-based immunotherapies. Here, we focus on elucidating the mechanisms of tumor intervention mediated by four tumor-infiltrating B lymphocytes. Naive B cells present the initial antigen, germinal center B cell subsets enhance antibody affinity, and immunoglobulin subtypes exert multiple immune effects, while regulatory B cells establish immune tolerance. Together they reflect the complexity of the changing dynamics of cancer immunity. Additionally, we have investigated the dynamic effects of tumor-infiltrating B lymphocytes in immunotherapy and their relationship to prognosis, providing new insights into potential treatment strategies for patients.

Cancer cells frequently rewire their metabolism to support proliferation and evade immune surveillance, but little is known about metabolic targets that could increase immune surveillance. Here we show a specific means of mitochondrial respiratory complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of either Ndufs4 or Ndufs6, but not other CI subunits, induces an immune-dependent growth attenuation in melanoma and breast cancer models. We show that deletion of Ndufs4 induces expression of the major histocompatibility complex (MHC) class I co-activator Nlrc5 and antigen presentation machinery components, most notably H2-K1. This induction of MHC-related genes is driven by a pyruvate dehydrogenase-dependent accumulation of mitochondrial acetyl-CoA, which leads to an increase in histone H3K27 acetylation within the Nlrc5 and H2-K1 promoters. Taken together, this work shows that selective CI inhibition restricts tumor growth and that specific targeting of Ndufs4 or Ndufs6 increases T cell surveillance and ICB responsiveness.

Recent developments in biomimetic nanoparticles, specifically carbohydrate polymer-coated cell membrane nanoparticles, have demonstrated considerable promise in treating cancer. These systems improve drug delivery by imitating natural cell actions, enhancing biocompatibility, and decreasing immune clearance. Conventional drug delivery methods frequently face challenges with non-specific dispersal and immune detection, which can hinder their efficiency and safety. These biomimetic nanoparticles improve target specificity, retention times, and therapeutic efficiency by using biological components like chitosan, hyaluronic acid, and alginate. Chitosan-based nanoparticles, which come from polysaccharides found in nature, have self-assembly abilities that make them better drug carriers. Hyaluronic acid helps target tissues more effectively, especially in cancer environments where there are high levels of hyaluronic acid receptors. Alginate-based systems also enhance drug delivery by being biocompatible and degradable, making them ideal choices for advanced therapeutic uses. Moreover, these particles hold potential for overcoming resistance to multiple drugs and boosting the body's immune reaction to tumors through precise delivery and decreased side effects of chemotherapy drugs. This review delves into the possibilities of using carbohydrate polymer-functionalized nanoparticles and their impact on enhancing the efficacy of cancer treatment.

Glioblastoma multiforme (GBM) is a highly invasive and fatal brain tumor with a grim prognosis, where current treatment modalities, including postoperative radiotherapy and temozolomide chemotherapy, yield a median survival of only 15 months. The challenges of tumor heterogeneity, drug resistance, and the blood-brain barrier necessitate innovative therapeutic approaches. This study introduces a strategy employing biomimetic magnetic nanorobots encapsulated with hybrid membranes derived from platelets and M1 macrophages to enhance blood-brain barrier penetration and target GBM. The nanorobots encapsulate a polypyrrole/Fe3O4 nanocomplex (PPy@F) for photothermal therapy (PTT) and promote the Fenton reaction of Fe3O4 to generate chemodynamic therapy (CDT). Additionally, temozolomide and PD-L1 antibody (SNTSESF) act as chemotherapy drug and immune checkpoint inhibitor, respectively. The biomimetic design leverages the functional properties of cell membranes to improve the blood residence time and tumor targeting. The integration of PTT and CDT aims to transform "cold" tumors into "hot" tumors, thereby enhancing immunotherapeutic efficacy. This multifaceted approach, PTT, CT, CDT, and immune checkpoint blockade therapy, offers a promising strategy for the treatment of GBM.

Cancer immunotherapy, which leverages the body's immune system to recognize and attack cancer cells, has made significant progress, particularly in the treatment of metastatic tumors. However, challenges such as drug stability and off-target effects still limit its clinical success. To address these issues, metal-organic frameworks (MOFs) have emerged as promising nanocarriers in cancer immunotherapy. MOFs have unique porous structure, excellent drug loading capacity, and tunable surface modification properties. MOFs not only enhance drug delivery efficiency but also allow for precise control of drug release. They reduce off-target effects and significantly improve targeting and therapy efficacy. As research deepens, MOFs' effectiveness as drug carriers has been refined. When combined with immunoadjuvants or anticancer drugs, MOFs further stimulate the immune response. This improves the specificity of immune attacks on tumors. This review provides a comprehensive overview of the applications of MOFs in cancer immunotherapy. It focuses on synthesis, drug loading strategies, and surface modifications. It also analyzes their role in enhancing immunotherapy effectiveness. By integrating current research, we aim to provide insights for the future development of immunoadjuvant-functionalized MOFs, accelerating their clinical application for safer and more effective cancer treatments.

Developing nanocarriers that can carry medications directly to tumors is an exciting development in cancer nanomedicine. The efficacy of this intriguing therapeutic approach is, however, compromised by intricate and immunosuppressive circumstances that arise concurrently with the onset of cancer. The artificial antigen presenting cell (aAPC), a micro or nanoparticle based device that mimics an antigen presenting cell by providing crucial signal proteins to T lymphocytes to activate them against cancer, is one cutting-edge method for cancer immunotherapy. This review delves into the critical design considerations for aAPCs, particularly focusing on particle size, shape, and the non-uniform distribution of T cell activating proteins on their surfaces. Adequate surface contact between T cells and aAPCs is essential for activation, prompting engineers to develop nano-aAPCs with microscale contact areas through techniques such as shape modification and nanoparticle clustering. Additionally, we explore recommendations for future advancements in this field.

Antibody-based checkpoint inhibitors have achieved great success in cancer immunotherapy, but their uncontrollable immune-related adverse events remain a major challenge. In this study, we developed a tumor-activated nanoparticle that is specifically active in tumors but not in normal tissues. We discovered a short anti-PD-L1 peptide that blocks the PD-1/PD-L1 interaction. The peptide was modified with a PEG chain through a novel matrix metalloproteinase-2 (MMP-2)-specific cleavage linker. The modified TR3 peptide self-assembles into a micelle-like nanoparticle (TR3-M-NP), which remains inactive and unable to block the PD-1/PD-L1 interaction in its native form. However, upon cleavage by MMP-2 in tumors, it releases the active peptide. The TR3-M-NP5k nanoparticle was specifically activated in tumors through enzyme-mediated cleavage, leading to the inhibition of tumor growth and extended survival compared to control groups. In summary, TR3-M-NP shows great potential as a tumor-responsive immunotherapy agent with reduced toxicities. STATEMENT OF SIGNIFICANCE: In this study, we developed a bioactive peptide-based checkpoint inhibitor that is active only in tumors and not in normal tissues, thereby potentially avoiding immune-related adverse effects. We discovered a short anti-PD-L1 peptide, TR3, that blocks the PD-1/PD-L1 interaction. We chemically modified the TR3 peptide to self-assemble into a micelle-like nanoparticle (TR3-M-NP), which itself cannot block the PD-1/PD-L1 interaction but releases the active TR3 peptide in tumors upon cleavage by MMP-2. In contrast, the nanoparticle is randomly degraded in normal tissues into peptides fragments that cannot block the PD-1/PD-L1 interaction. Upon intraperitoneal injection, TR3-M-NP5k was activated specifically in tumors through enzyme cleavage, leading to the inhibition of tumor growth and extended survival compared to the control groups. In summary, TR3-M-NP holds significant promise as a tumor-responsive immunotherapy agent with reduced toxicities. The bioactive platform has the potential to be used for other types of checkpoint inhibitor.

The impact of radiation-related lymphocyte recovery on prognosis in locally advanced esophageal squamous cell carcinoma (LA-ESCC) remains unclear.

Patients with stage II-IVa ESCC who received definitive RT were screened. Collect absolute lymphocyte counts (ALCs) before, during, and after RT. The recovery status of lymphocytes was observed at one-month post-RT (P1) and three months post-RT (P3). Patients with relatively lower lymphocyte recovery levels at P1 were divided into Group a and those with higher levels were divided into Group b. Patients with relatively lower lymphocyte recovery levels at P3 were divided into Group A and those higher were divided into Group B. Kaplan-Merier's analysis and Cox analysis were conducted to compare survival outcomes. Binary logistic regression analyses was employed to ascertain factors associated with lymphocyte recovery.

116 patients were enrolled. During RT, ALCs reached the bottom 5 weeks after RT started and 70.7% of patients experienced G3 lymphopenia. The median OS for Group a and Group b were 38.1 months and 14.4 months, p = 0.097. The median PFS for Group a and Group b were 14.2 months and 10.0 months, p = 0.037. Whereas, the median OS for Group A and Group B was 14.5 months and 22.2 months, p = 0.019. The median PFS for Group A and Group B were 8.4 months and 12.4 months, p = 0.021. Cox multivariable analysis revealed that higher lymphocyte recovery level at P3 was significantly associated with superior OS (p = 0.040, HR0.636) and PFS (p = 0.028, HR0.627). The logistic analysis identified a positive association between G4 lymphopenia during RT (p = 0.012, OR 7.742) and PTV dose < 60 Gy (p = 0.014, OR 2.655) with lymphocyte recovery.

The prognostic value of lymphocyte recovery status at P3 appears to be greater than that of lymphocyte recovery status at P1 for locally advanced ESCC patients. Radiation-related lymphocyte recovery might serve as a valuable prognostic factor in LA-ESCC.

Oncogenes are typically overexpressed in tumor tissues and often linked to poor prognosis. However, recent advancements in bioinformatics have revealed that many highly expressed genes in tumors are associated with better patient outcomes. These genes, which act as tumor suppressors, are referred to as "paradoxical genes." Analyzing The Cancer Genome Atlas (TCGA) confirmed the widespread presence of paradoxical genes, and KEGG analysis revealed their role in regulating tumor metabolism. Mechanistically, discrepancies between gene and protein expression-affected by pre- and post-transcriptional modifications-may drive this phenomenon. Mechanisms like upstream open reading frames and alternative splicing contribute to these inconsistencies. Many paradoxical genes modulate the tumor immune microenvironment, exerting tumor-suppressive effects. Further analysis shows that the stage- and tumor-specific expression of these genes, along with their environmental sensitivity, influence their dual roles in various signaling pathways. These findings highlight the importance of paradoxical genes in resisting tumor progression and maintaining cellular homeostasis, offering new avenues for targeted cancer therapy.

Utilizing the cGAS-STING pathway to combat immune evasion is one of the most promising strategies for enhancing cancer immunotherapy. However, current techniques for activating the cGAS-STING pathway often face a dilemma, mainly due to the balance between efficacy and safety. Here, we develop a uracil base lesion-gated dumbbell DNA nanodevice (UBLE) that allows on-demand activation and termination of the cGAS-STING pathway in tumor cells, thereby enhancing cancer immunotherapy. The UBLE integrates two deoxyuridines (dU) in the stem for DNA lesion recognition, two locked complementary primer sequences (primers A and B) for DNA self-assembly, and a Förster resonance energy transfer pair (Cy3 and Cy5) attached to the loop for activation assessment. Upon the orthogonal recognition of tumor-specific repair indicators (UDG and APE1), the UBLE undergoes a conformational change to create massive nicked double-stranded DNA (dsDNA) units. These units self-assemble to generate long fluorescent dsDNA structures, permitting selective evaluation and on-demand activation of the cGAS-STING pathway. Furthermore, we demonstrate that the UBLE can effectively activate the cGAS-STING pathway in tumor cells, enhancing NK cell-targeted cancer immunotherapy. This work develops a DNA lesion-gated strategy for on-demand activation and termination of the cGAS-STING pathway, affording an innovative avenue for enhancing cancer immunotherapy.

The interpretation of the biochemistry of immune metabolism could be considered an attractive scientific field of biomedicine research. In this review, the role of glycolysis in macrophage polarization is discussed together with mitochondrial metabolism in cancer cells. In the first part, the focus is on the Warburg effect and redox metabolism during macrophage polarization, cancer development, and management of the immune response by the cancer cells. The second part addresses the possibility of impacts on the Warburg effect through targeting peroxisome proliferator-activated receptors (PPARs). This could be an activator of native immune responses. Because of the reported serious adverse effects of using synthetic ligands for PPARs in combination with chemotherapeutics, searches for less toxic and more active PPAR inhibitors, as well as blocking undesirable cellular PPAR-dependent processes, are in progress. On the other hand, recent research in modern immunotherapy has focused on the search for gentle immune-modulating natural compounds with harmless synergistic chemotherapeutic efficacy that can be used as an adjuvant. It is a well-known fact that the plant kingdom is a source of important therapeutic agents with multifaceted effectiveness. One of these is the known association with PPAR activities. In this regard, the secondary metabolites extracted from plants could change the game.

Antigen processing and presentation via major histocompatibility complex (MHC) molecules are central to immune surveillance. Yet, quantifying the dynamic activity of MHC class I and II antigen presentation remains a critical challenge, particularly in diseases like cancer, infection and autoimmunity where these pathways are often disrupted. Current methods fall short in providing precise, sample-specific insights into antigen presentation, limiting our understanding of immune evasion and therapeutic responses. Here, we present PSAA (PINN-empowered Systems Biology Analysis of Antigen Presentation Activity), which is designed to estimate sample-wise MHC class I and class II antigen presentation activity using bulk, single-cell, and spatially resolved transcriptomics or proteomics data. By reconstructing MHC pathways and employing pathway flux estimation, PSAA offers a detailed, stepwise quantification of MHC pathway activity, enabling predictions of gene-specific impacts and their downstream effects on immune interactions. Benchmarked across diverse omics datasets and experimental validations, PSAA demonstrates a robust prediction accuracy and utility across various disease contexts. In conclusion, PSAA and its downstream functions provide a comprehensive framework for analyzing the dynamics of MHC antigen presentation using omics data. By linking antigen presentation to immune cell activity and clinical outcomes, PSAA both elucidates key mechanisms driving disease progression and uncovers potential therapeutic targets.

Cancer immune responses are generated in secondary lymphoid organs, such as the lymph nodes and tonsils. In the current study, transcriptional profiles of peritumoral tonsillar tissues (PTTs) from oropharyngeal cancers (OPCs) were assessed and compared with those of inflammatory tonsils and regional lymph nodes (rLNs).

RNA samples of PTTs and rLNs from 13 OPCs, and 4 inflammatory tonsils were subjected to microarray analysis, and differentially expressed genes (DEGs) identified from 730 nCounter Panel immune-related genes. Gene Set enrichment Analysis (GSEA) was used for DEG profiling of PTTs and rLNs between lymph node metastasis-negative and metastasis-positive cases. The top 20 genes, as ranked by GSEA metric scores, were extracted and subjected to principal component analysis (PCA). The correlation of each patient's PCA score with lymph node status was assessed by Receiver Operating Characteristics (ROC) analysis.

Comparing DEG analyses of PTTs with those of inflammatory tonsils and rLNs revealed 144 and 45 upregulated genes, respectively. ClueGO, a widely used Cytoscape plug-in, revealed activated pathways in PTTs, including lymphocyte proliferation (followed by T cell activation involved in the immune response) and positive regulation of leukocyte migration (followed by antimicrobial humoral immune response mediated by antimicrobial peptides) as the most significantly enriched immune system process functions in the gene ontology when comparing inflammatory tonsils and rLNs. The area under the ROC curves of PTTs and rLNs were 0.806 and 0.389, and were significant by DeLong's test (p = 0.025).

PTTs exhibit unique immunological features distinguishing them from inflammatory tonsils and rLNs. Gene expression analysis of PTTs is useful for investigating the mechanism of OPC lymphatic spread, even compared with analysis of rLNs.

Increased PD-1 expression on CD8+ T cells is considered as a hallmark for T-cell exhaustion, and is thought to be related to the prognosis of cancer patients. However, discrepant results have made it difficult to apply PD-1+CD8+T cells and tumor prognosis to clinical practice. Therefore, we conducted a meta-analysis to evaluate its prognostic value in human cancers.

PRISMA reporting guidelines were strictly followed for conducting the current meta-analysis. The PubMed, Web of Science, Embase databases were searched from inception to November 2024. The pooled Hazard Ratio (HR) along with 95% confidence intervals (CIs) of each article were combined for the associations of PD-1+CD8+ T cells with overall survival (OS), progression- free survival (PFS) and disease-free survival(DFS). Subgroup analyses were performed for area, specimen type, cancer type, treatment, detected method and cancer stage.

A total of 20 studies (23 cohorts, 3086 cancer patients) were included in our study. The expression PD-1+CD8+ T cells in cancer patients tended to predict poor overall survival (OS) (HR: 1.379, 95%CI: 1.084-1.753, p= 0.009), and unfavorable disease-free survival(DFS) (HR: 1.468, 95%CI: 0.931-2.316, p=0.099), though it did not reach statistical significance. Begg's and Egger's test demonstrated that no obvious publication bias was exist.

High PD-1 expression on CD8+ T cells is associated with worse survival outcomes, which can be potentially used as a prognostic marker of malignant tumor.

As research progresses, our understanding of the tumor microenvironment (TME) has undergone profound changes. The TME evolves with the developmental stages of cancer and the implementation of therapeutic interventions, transitioning from an immune-promoting to an immunosuppressive microenvironment. Consequently, we focus intently on the significant role of the TME in tumor proliferation, metastasis, and the development of drug resistance. AXL is highly associated with tumor progression; however, previous studies on AXL have been limited to its impact on the biological behavior of cancer cells. An increasing body of research now demonstrates that AXL can influence the function and differentiation of immune cells, mediating immune suppression and thereby fostering tumor growth. A comprehensive analysis to identify and overcome the causes of immunosuppressive microenvironments represents a novel approach to conquering cancer. In this review, we focus on elucidating the role of AXL within the immunosuppressive microenvironments, discussing and analyzing the effects of AXL on tumor cells, T cells, macrophages, natural killer (NK) cells, fibroblasts, and other immune-stromal cells. We aim to clarify the contributions of AXL to the progression and drug resistance of cancer from its functional role in the immune microenvironment.

Tertiary lymphoid structures (TLSs) are organized ectopic lymphoid aggregates within the tumor microenvironment that serve as crucial sites for the development of adaptive antitumor cellular and humoral immunity. TLSs have been consistently documented in numerous cancer types, correlating with improved prognosis and enhanced responses to immunotherapy, especially immune-checkpoint blockade (ICB). Given the potential role of TLSs as predictive biomarkers for the efficacy of ICB in cancer patients, the therapeutic manipulation of TLSs is gaining significant attention as a promising avenue for cancer treatment. Herein, we comprehensively review the composition, definition, and detection methods of TLSs in humans. We also discuss the contributions of TLSs to antitumor immunity, their prognostic value in cancer patients, and their association with therapeutic response to ICB-based immunotherapy. Finally, we present preclinical data supporting the potential of therapeutically manipulating TLSs as a promising approach for innovative cancer immunotherapy.

Granzyme A (GzmA) secreted by natural killer (NK) cells has garnered considerable interest as a biomarker to evaluate the efficacy of cancer immunotherapy. However, current methodologies to selectively monitor the spatial distribution of GzmA in cancer cells during NK cell-targeted therapy are extremely challenging, primarily due to the existence of diverse cell populations, the low levels of GzmA expression, and the limited availability of GzmA probes. Herein we develop a multi-modular, structurally-ordered DNA nanodevice for evaluating NK cell-mediated cancer immunotherapy (MODERN), that permits spatioselective imaging of GzmA in cancer cells through GzmA-induced apurinic/apyrimidinic endonuclease 1 (APE1) inactivation. The MODERN incorporates multiple functional modules, including an APE1-gated recognition module, a photo-activated amplification module, an aptamer-mediated tumor-target module, and a polycatenane DNA module, enabling improved sensitivity and specificity towards intracellular GzmA. The MODERN was activated (on) in cancer cells due to the overexpression of APE1, whereas it remained silent (off) in the NK-treated cancer cells owing to the GzmA-induced APE1 inactivation. Furthermore, we demonstrated that GzmA-induced APE1 inactivation blocks the cellular repair of target cells, resulting in efficient cell death. This MODERN that relies on the specific inactivation of APE1 by GzmA should be beneficial for evaluating the efficacy of cancer immunotherapy.