Despite the tremendous success in preclinical models, the translation of human mesenchymal stromal cells (hMSCs) as a therapy in the clinic is not up to the expectation. Intrinsic factors (age, sex, health status, life style of the donor, source, cellular senescence, and oxidative stress in hMSCs), extrinsic factors (culture system, batch-to-batch variations, choice of biomaterials, cell processing and preservation protocols), and host microenvironment (inflammatory milieu, oxidative stress, and hypoxia in the recipient) compromise the overall therapeutic efficacy of the transplanted hMSCs. In recent times, the approach of 'Disease Microenvironment Preconditioning (DMP)' has garnered attention to overcome the host-associated attributes involved in compromised hMSCs therapeutic potential. In this review, we discuss various approaches of DMP of hMSCs by employing serum and other body fluids obtained from diseased patients/animals and small molecules, including cytokines such as IFN-γ, IL-6, IL-10, IL- β, TGF-β1, IL-1α, IL-1β, TNF-α, HMGB1, IL-17 A, and IL-8 which are associated with disease conditions. DMP strengthens hMSCs ability to adapt/acclimatize and respond more efficiently to the hostile microenvironment they encounter upon transplantation. DMP modulate hMSCs to withstand inflammation, survive under hypoxic and nutrient-deprived conditions, and resist oxidative stress. Evidence from various disease models ranging from cardiovascular and neurodegenerative disorders to autoimmune diseases and tissue injuries supports the role of DMP in improving hMSC survival, integration, and functional efficacy. While the potential of DMP to revolutionize MSC-based therapies is evident, challenges such as standardizing/optimizing protocols for preconditioning is essential. This review synthesizes current advancements in the approach of DMP aiming to propel the area of regenerative medicine.

Melanoma is one of the most commonly diagnosed malignancies and serves as a model for studying immunotherapy. The B16 melanoma model, resembling human cold tumors that lack T cell infiltration and show minimal response to PD-1 blockade, is widely used for studying melanoma and its resistance to immunotherapy. Therefore, understanding the molecular basis that prevents T cell-mediated anti-tumor activity in B16 melanoma is of great significance.

In this study, we generated tyrosinase knockout B16 melanoma cells using CRISPR/Cas9 and discovered that tyrosinase in melanoma significantly inhibits the anti-tumor activity of T cells. Tyrosinase deficiency leads to a 3.80-fold increase in T-cell infiltration and enhances T-cell activation within the tumor. Single-cell RNA sequencing reveals an altered cold tumor immunophenotype in tyrosinase-deficient B16 melanoma. In wild-type mice, T cells in tyrosinase-deficient tumors express elevated levels of PD-1 and Foxp3. However, strikingly, in PD-1 deficient mice, the loss of tyrosinase in B16 melanoma unleashes the anti-tumor activity of PD-1 deficient T cells. This enhanced anti-tumor activity is explained by significantly increased tumor T cell infiltration accompanied by reduced frequencies of regulatory T cells in PD-1 knockout mice.

These findings suggest that targeting tyrosinase could convert cold tumors into an immune-responsive state in vivo using murine models. Inhibiting tyrosinase could enhance the effectiveness of PD-1 blockade, offering a new approach for melanoma patients who fail in current PD-1 inhibitor treatment.

Tumor necrosis factor-α (TNF-α) is a crucial cytokine involved in cancer progression, affecting the proliferation and survival of tumor cells. However, the exact mechanisms underlying its action remain poorly understood. Here we found that high concentration of TNF-α decreased TNF-α and heterogenous nuclear ribonucleoprotein L related immunoregulatory LncRNA (THRIL) expression, thereby inhibiting non-small cell lung cancer (NSCLC) cells proliferation while facilitating apoptosis. Clinically, the expression of THRIL was upregulated in NSCLC cells and tissues. THRIL knockdown resulted in decreased proliferation and increased apoptosis in NSCLC cells. Mechanistically, TNF-α diminished the m6A methylation of the THRIL transcript by enhancing the expression of FTO in A549 cells, which was subsequently recognized and degraded by YTHDF2. Furthermore, we identified that THRIL specifically interacted with HuR, forming a functional THRIL-HuR complex that enhanced TNF-α mRNA stability, thereby influencing endogenous TNF-α expression. Collectively, our findings reveal a novel regulatory feedback loop between TNF-α and THRIL, demonstrating that TNF-α inhibits the proliferation of NSCLC cells via the FTO/YTHDF2/THRIL axis. This highlights THRIL as a potential biomarker and therapeutic target in NSCLC.

Melanoma, driven by defective immune surveillance and cancer-cell evasion, has rising morbidity and mortality due to solar radiation exposure and delayed diagnosis. Effective tumor opsonization and phagocytosis are needed, demanding new therapeutic formulations. Here, we demonstrate the efficacy of a novel lipid-coated glucose nanosphere (LGNP) formulation decorated with ovalbumin (OVA) and containing pCMV-MART-1 (MT-1), termed the nLOM vaccine. This vaccine elicits specific immune responses through bone marrow DC maturation and CD4+/CD8+ T-cell activation, targeting melanoma antigens. In preclinical studies using orthotopic B16-F10 melanoma cells in C57BL/6J mice, the vaccine induced significant infiltration of T lymphocytes into tumor tissues, reducing tumor progression. Robust immune responses were observed in the spleens and inguinal lymph nodes of vaccinated mice, characterized by elevated cytokine levels. These findings suggest that the nLOM vaccine could elicit durable immunogenicity against melanoma through enhanced antigen presentation and holds promise for clinical development as an effective immunotherapy.

Gamma delta (γδ) T cells are a unique subset of T lymphocytes with distinctive features that make them highly promising candidates for cancer therapy. Their MHC-independent recognition of tumor antigens, ability to mediate direct cytotoxicity, and role in modulating the tumor microenvironment position them as versatile agents in cancer immunotherapy. This review integrates and synthesizes the existing data on γδ T cells, with an emphasis on the development and optimization of in vitro expansion protocols. Critical aspects are detailed such as activation strategies, co-culture systems, cytokine use, and other parameters to ensure robust cell proliferation and functionality, which may be valuable for those developing or optimizing clinical practices. Finally, we discuss current advancements in γδ T cell research, clinical experience, and highlight areas needing further exploration. Considering these data, we hypothesize and propose potential new applications such as engineering γδ T cells for enhanced resistance to immune checkpoint pathways or for localized cytokine delivery within the tumor microenvironment, which could broaden their therapeutic impact in the treatment of cancer and beyond.

In the tumor immunosuppressive microenvironment (TIME), regulatory T cells (Tregs) critically suppress anticancer immunity, characterized by high expression of glucocorticoid-induced TNF receptor (GITR) expression and sensitivity to reactive oxygen species (ROS). This study develops a near-infrared (NIR)-responsive hollow nanocomplex (HPDA-OPC/DTA-1) using hollow polydopamine nanoparticles (HPDA), endowed with thermogenic and antioxidative properties, specifically targeting Tregs to activate antitumor immunity. The GITR agonist DTA-1, combined with the antioxidant oligomeric proanthocyanidins (OPC) to deplete Tregs. However, Tregs depletion alone may not sufficiently trigger robust immune responses. The HPDA nanocarrier enhances thermogenic and antioxidative capacities, supporting photothermal immunotherapy. The HPDA-OPC/DTA-1 demonstrates NIR responsiveness for both photothermal therapy (PTT) and OPC release, while facilitating Tregs depletion via DTA-1 and reducing ROS levels, thereby reviving antitumor immunity. Notably, intratumoral CD4+CD25+FOXP3+ Tregs exhibited a 4.08-fold reduction alongside a 49.11-fold increase in CD8+ T cells/Tregs relative to controls. Enhanced dendritic cells (DCs) maturation and immunogenic cell death (ICD) induction further demonstrate that HPDA-OPC/DTA-1 alleviates immunosuppression and activates antitumor immunity. Ultimately, the observed tumor inhibitory effect (tumor volume: 6.75-fold versus the control) and an over 80% survival rate highlight the therapeutic potential of combining Tregs targeting, antioxidant strategy, and photothermal immunotherapy for effective cancer treatment.

Although the mono-anticancer therapy approach particularly directly targeting tumors is still common, this conventional method is generally deemed not effective and insufficient. In tumor microenvironment (TME), tumor-associated macrophages (TAMs, referred to as M2-polarized) play a crucial role in creating an immunosuppressive TME, contributing to various pro-tumorigenic effects. A promising strategy to inhibit tumor growth involves re-educating M2 macrophages into tumoricidal macrophages (M1). Therefore, combining macrophage reprogramming with cancer cell death induction in a single modality may offer synergistic benefits in cancer therapy. Here, we engineered a lipid-based delivery platform capable of co-delivering resiquimod (R848) and polyinosinic: polycytidylic acid (PIC). R848 in our nanosystem effectively triggered M2-to-M1 repolarization, as evidenced by the upregulation of M1 marker genes (TNF, IL6), the release of proinflammatory cytokines (TNF-α and IL-6), and the downregulation of the M2 marker gene, MRC1. On the other hand, the presence of PIC increased caspase-3/7 activity leading to cancer cell death through the apoptotic pathway. This nanocarrier system established a multifunctional platform to enhance the anticancer effect. The synergistic effect of repolarized macrophages in combination with the induction of apoptosis, facilitated by our nanomedicine, was evident in a co-culture system of macrophage and cancer cells, showing a significant increase in cancer cell death compared to individual treatments. These findings attractively demonstrated the potential of our multifunctional lipid nanoparticles as therapeutic agents for anticancer treatment by modulating the tumor immune microenvironment and simultaneously increasing cancer cell cytotoxicity.

Several steps of cancer progression, from tumor onset to metastasis, critically involve proteolytic activity. To elucidate the role of proteases in cancer, it is particularly important to consider single-nucleotide variants (SNVs) that affect the active site of proteases, thereby influencing cleavage specificity, substrate processing, and thus cancer cell behavior. To facilitate systematic studies, we here present a targeted approach to determine the impact of cancer-associated protease variants (TACAP). Starting with the semiautomated identification of potential specificity-modulating SNVs, our workflow comprises mass spectrometry-based cleavage specificity profiling and substrate identification, localization, and inhibitor studies, followed by functional analyses investigating cancer cell properties. To demonstrate the feasibility of TACAP, we analyzed the meprin β R238Q variant. This amino acid exchange R238Q leads to a loss of meprin β's characteristic cleavage preference for acidic amino acids at P1' position, accompanied with changes in substrate pool and inhibitor affinity compared to meprin β wild type.

Cancer-associated fibroblasts (CAFs) secrete and synthesize fibroblast activation protein (FAP), which could promote proliferation and immunosuppression of multiple cancers including esophageal squamous cell carcinoma (ESCC). CXCL12/CXCR4 signaling could be revitalized by CAFs in cancer cells. Nevertheless, the significance of this interaction in ESCC has yet to be elucidated. Herein, we investigated whether FAP+ CAF cells could promote ESCC cells proliferation, migration and regulate immunity through the CXCL12/CXCR4 pathway in vitro and in vivo. The protein expression level of FSP1, FAP, CD8+ and Ki-67 in different sample was estimated by IHC and western blot. qPCR was used to quantify the mRNA level of FSP1, FAP, CD8+ and Ki-67 in different sample. The cell viability, proliferation, migration and invasion of different sample were evaluated by CCK-8, EdU staining, wound healing assay and Transwell assay, respectively. The ELISA was carried out to measure the protein level of IFN-γ, TNF-α, GZMB and IL-2. ESCC xenograft mice model was established to assess the impact of FAP+ CAF. FSP1, FAP, CD8+ and Ki-67 are greatly up-regulated in hESCC tissues. Through CXCL12/CXCR4 axis, FAP-positive CAF was capable of promoting the cell proliferation, migration and invasion of ESCC tumor cells and preventing the CD8+ T cells from secreting cytokine. Blocking this signaling with selective CXCR4 antagonist could counteract the effects caused by high-expression of FAP. FAP+ CAFs could inhibit the occurrence and development of tumors. These results indicated that FAP-positive CAF have an impact on cell proliferation migration and immunoregulation of ESCC through the CXCL12/CXCR4 axis.

Chronic low-grade inflammation, often observed in hypertrophic cardiomyopathy (HCM), promotes adverse ventricular remodelling. This study aimed to investigate the relationship between inflammatory markers and myocardial fibrosis (MF) in patients with HCM.

This study included 102 patients with complete baseline data who underwent septal myectomy. Myocardial samples were stained with Masson's trichrome and analysed to determine myocardial collagen content and MF levels. Plasma levels of inflammatory markers were measured using standard laboratory procedures. Univariate and multivariate logistic regression analyses were performed to explore the relationship between the inflammatory markers and MF. Among the 102 participants included in the analysis, the mean age was 48.9 years, with 69 [67.6%] being men. The overall MF ranged from 2.5% to 40.7% (mean = 15.2 ± 8.1%, median = 13.0%, IQR = 9.9%-18.4%). Participants were divided into two groups based on a median MF of 13%. The high MF group had a larger left atrial diameter and left ventricular ejection fraction. Levels of interleukin (IL)-2, tumour necrosis factor (TNF)-α and interferon (IFN)-α were significantly higher in patients with high MF compared to those with low MF (2.3 vs. 4.0 pg/mL, 3.1 vs. 3.9 pg/mL, 4.2 vs.4.7 pg/mL, respectively; all P < 0.05). In multivariate models adjusted for age, sex and other clinical features, IL-2, IL-5 and TNF-α, were correlated with increased interstitial MF [odds ratio (OR): 1.54, 95% confidence interval (CI): 1.10-2.14; OR: 1.42, 95% CI: 1.02-1.98; OR: 1.33, 95% CI: 1.04-1.70]. After additional adjustment for imaging indicators, IL-2 and TNF-α remained significant (OR: 1.49, 95% CI: 1.06-2.09, P = 0.021; OR:1.35, 95% CI: 1.01-1.80, P = 0.044). The correlation analysis between inflammation and replacement fibrosis assessed by CMR in 97 patients revealed that 72 (74.2%) showed late gadolinium enhancement (LGE). No significant correlation was found between inflammatory markers and the presence or extent of LGE.

Higher levels of IL-2 and TNF-α were associated with increased histopathological interstitial MF in patients with HCM. Given the gradual progression of MF in HCM, initiating anti-inflammatory treatment in the early stages may delay its progression.

Compared with all other cancer types, Breast cancer (BC) among women has now exceeded them all as the primary reason for cancer worldwide. The BC represents 11.7% of all cancer cases and accounts for a predestined 2.3 million new cases. It is the fourth primary reason for cancer-associated deaths in women. With a staggering 200-400% increase in the relative incidence of BC in Egypt, there is an urgent need for new diagnostic or predictive markers.

The current investigation aims to explore the connection of the functional TNF-α-308G > A (rs1800629) single-nucleotide polymorphism (SNP) with different breast cancer predictive indices.

The ARMS-PCR method was used for genotyping TNF-α-308G > A SNP. Three groups were recruited for the study: 79 patients with benign breast inflammation (BBI); 163 with breast cancer (BC) and 144 controls (C).

The TNF-α-308G > A SNP was distributed among different groups in a unique pattern; in the control group 63.9% of cases were in the GG, 34% were in the GA, and 2.1% were in the AA. The BC group had 14% GG, 79% GA, and 7% AA, while the BBI group had 24% GG, 76% GA, and 0% AA. The AA genotype and A allele represented a strong significant correlation with risk factors in the BC group (ORAA: 14.67 [95% CI = 3.78-56.91] and ORA: 0.27 [95% CI = 0.19-0.39], respectively; P < 0.0001) in contrast to the control group. However, in the BBI group, a strong significant correlation was noted with the GA genotype (ORGA: 5.93 [95% CI = 3.18-11.04] P < 0.0001). In the BC group, the AA genotype shows a significant increase in Nottingham Prognostic Index (NPI) in positive ER and PR in contrast to the relevant negative ones (P = 0.02 and 0.002, respectively). However, the GA genotype significantly increased NPI in positive Her2 and metastatic patients (P = 0.03 and 0.01, respectively).

This research is the first to correlate TNF-α-308G > A (rs1800629) SNP in Egyptian BC patients. The A allele, GA & AA genotypes, and the Overdominant model of the TNF-α-308G > A gene variants were recorded as prognostic risk factors for BC carcinogenesis.

Oncolytic virus (OV) mediated immunotherapy is one of the recent techniques used to treat higher grade cancers where conventional therapies like chemotherapy, radiation fail. OVs as a therapeutic tool show high efficacy and fewer side effects than conventional methods as supported by multiple preclinical and clinical studies since they are engineered to target tumours. In this chapter, we discuss the modifications in viruses to make them oncolytic, types of strains commonly administered, mechanisms employed by viruses to specifically target and eradicate malignancy and progress achieved as reported in case studies (preclinical and clinical trials). OVs also face some unique challenges with respect to the malignancy being treated and the varied pathogen exposure of the patients, which is also highlighted here. Since pathogen exposure varies according to population dynamics worldwide, chances of generating a non-specific recall response to an OV cannot be negated. Lastly, the future perspectives and ongoing practises of combination therapies are discussed as they provide a leading edge over monotherapies in terms of tumour clearance, blocking metastasis and enhancing patient survival. Efforts undertaken to overcome current challenges are also highlighted.

Lymph node (LN) targeting and antigen presentation by antigen-presenting cells (APCs) are critical factors affecting the immune responses induced by tumor vaccines. Autophagy activation promotes MHC class I and II antigen presentation in APCs. To enhance antigen presentation in LNs, we developed an aluminum hydroxide nanovaccine that simultaneously incorporates the autophagy-activating peptide Beclin-1 and the antigenic protein OVA (B/O@AN nanovaccine) through layer-by-layer electrostatic interaction. B/O@AN has a particle size of approximately 80 nm and efficiently targets lymph nodes following subcutaneous administration. The combination of the Beclin-1 peptide with the aluminum hydroxide nanovaccine promotes dendritic cell (DC) maturation. More importantly, B/O@AN facilitates antigen cross-presentation by promoting lysosomal escape and autophagy induction. After immunization, compared to O/@AN without Beclin-1, B/O@AN significantly augments antigen-specific cellular immune responses, leading to substantial increases in cytotoxic T lymphocytes (CTLs), T-helper 1 (Th1) cells, as well as serum antibody levels, thereby impeding melanoma development and progression in both prophylactic and therapeutic settings. These results provide evidence that autophagy activation strengthens antigen presentation and augments the antigen-specific immune responses of the aluminum hydroxide nanovaccine.

The discovery of tertiary lymphoid structures (TLS) within tumor tissues provides a promising avenue to promote the efficacy of cancer immunotherapy. Yet, the lack of effective strategies to induce TLS formation poses a substantial obstacle. Thus, the exploration of potential inducers for TLS formation is of great interest but remains challenging. Here, inspired by the mechanism of artificially cultivated pearls, a covalent organic framework (COF) is employed to induce TLS formation. Single-cell sequencing analysis reveals that this is achieved by promotion of cytokine hypersecretion, which facilitates the maturation, proliferation, and migration of T and B cells, critical for triggering TLS formation. Furthermore, the efficacy of COF-mediated phototherapy in inducing TLS formation is validated in both the MC38 and 4MOSC1 female tumor models. Notably, a strong synergistic effect between COF-mediated phototherapy and αCTLA-4 is observed, resulting in the effective eradication of both primary and distant tumors, while also inhibiting tumor recurrence.

Intimal sarcoma is a rare and aggressive soft-tissue sarcoma with limited treatment options. We explored genomic profiles of intimal sarcoma to uncover therapeutic implications.

We analyzed tumor tissues from patients with intimal sarcoma who visited the Seoul National University Hospital (SNUH) using whole-exome, whole-transcriptome, and clinical next-generation sequencing (NGS), integrated with intimal sarcoma NGS data from two public cohorts. We examined expression characteristics and tumor-infiltrating lymphocytes (TILs) according to molecular subtypes.

Our study included 42 samples in total. Thirty-three patients showing copy number variation (CNV) enrichment with frequent CDK4/MDM2 amplifications were classified as the CNV-high (CNV-H) subtype. Five patients showing predominant MLH1 mutations or homozygous deletions were classified as the microsatellite instability-high-like (MSI-H-like) subtype. Hallmark pathways up-regulated in the CNV-H subtype included Wnt β-catenin and Hedgehog signaling. In the MSI-H-like subtype, interferon-γ response, tumor necrosis factor-α signaling via nuclear factor-κB, interferon-α response, inflammatory response, and interleukin-6-Jak-Stat3 signaling were up-regulated. CNV-H subtype samples predominantly showed an immune-desert phenotype, whereas MSI-H-like subtype samples predominantly showed an immune-inflamed phenotype. Two MSI-H-like subtype patients received pembrolizumab and experienced tumor shrinkage.

We identified two intimal sarcoma molecular subtypes. Compared with CNV-H, MSI-H-like is enriched in pathways associated with tumor immune responses and TILs. Further efforts and clinical trials to better define these molecular subtypes are warranted to open new avenues for personalized treatment approaches and improve patient outcomes.

Immune checkpoint inhibitors have shaped the landscape of cancer treatment. However, many patients either do not respond or suffer from later progression. Numerous proteins can control immune system activity, including multiple tumor necrosis factor (TNF) superfamily (TNFSF) and TNF receptor superfamily (TNFRSF) members; these proteins play a complex role in regulating cell survival and death, cellular differentiation, and immune system activity. Notably, TNFSF/TNFRSF molecules may display either pro-tumoral or anti-tumoral activity, or even both, depending on tumor type. Therefore, TNF is a prototype of an enigmatic two-faced mediator in oncogenesis. To date, multiple anti-TNF agents have been approved and/or included in guidelines for treating autoimmune disorders and immune-related toxicities after immune checkpoint blockade for cancer. A confirmed role for the TNFSF/TNFRSF members in treating cancer has proven more elusive. In this review, we highlight the cancer-relevant TNFSF/TNFRSF family members, focusing on the death domain-containing and co-stimulation members and their signaling pathways, as well as their complicated role in the life and death of cancer cells.

The treatment of head and neck tumors remains a challenge due to their reduced radiosensitivity. Small molecule kinase inhibitors (smKI) that inhibit the DNA damage response, may increase the radiosensitivity of tumor cells. However, little is known about how the immunophenotype of the tumor cells is modulated thereby. Therefore, we investigated whether the combination of ATM or ATR inhibitors with hypo-fractionated radiotherapy (RT) has a different impact on the expression of immune checkpoint markers (extrinsic), the release of cytokines or the transcriptome (intrinsic) of head and neck squamous cell carcinoma (HNSCC) cells.

The toxic and immunogenic effects of the smKI AZD0156 (ATMi) and VE-822 (ATRi) in combination with a hypo-fractionated scheme of 2x5Gy RT on HPV-negative (HSC4, Cal-33) and HPV-positive (UM-SCC-47, UD-SCC-2) HNSCC cell lines were analyzed as follows: cell death (necrosis, apoptosis; detected by AnxV/PI), expression of immunostimulatory (ICOS-L, OX40-L, TNFSFR9, CD70) and immunosuppressive (PD-L1, PD-L2, HVEM) checkpoint marker using flow cytometry; the release of cytokines using multiplex ELISA and the gene expression of Cal-33 on mRNA level 48 h post-RT.

Cell death was mainly induced by the combination of RT with both inhibitors, but stronger with ATRi. Further, the immune phenotype of cancer cells, not dying from combination therapy itself, is altered predominantly by RT+ATRi in an immune-stimulatory manner by the up-regulation of ICOS-L. However, the analysis of secreted cytokines after treatment of HNSCC cell lines revealed an ambivalent influence of both inhibitors, as we observed the intensified secretion of IL-6 and IL-8 after RT+ATRi. These findings were confirmed by RNAseq analysis and further the stronger immune-suppressive character of RT+ATMi was enlightened. We detected the down-regulation of a central protein of cytoplasmatic sensing pathways of nucleic acids, RIG-1, and found one immune-suppressive target, EDIL3, strongly up-regulated by RT+ATMi.

Independent of a restrictive toxicity, the combination of RT + either ATMi or ATRi leads to comprehensive and immune-modulating alterations in HNSCC. This includes pro-inflammatory signaling induced by RT + ATRi but also anti-inflammatory signals. These findings were confirmed by RNAseq analysis, which further highlighted the immune-suppressive nature of RT + ATMi.

Cancers eventually kill hosts even when infiltrated by cancer-specific T cells. We examined whether cancer-specific T cell receptors of CD4+ T cells (CD4TCRs) from tumor-bearing hosts can be exploited for adoptive TCR therapy. We focused on CD4TCRs targeting an autochthonous mutant neoantigen that is only presented by stroma surrounding the MHC class II-negative cancer cells. The 11 most common tetramer-sorted CD4TCRs were tested using TCR-engineered CD4+ T cells. Three TCRs were characterized by convergent recombination for which multiple T cell clonotypes differed in their nucleotide sequences but encoded identical TCR α and β chains. These preferentially selected TCRs destroyed tumors equally well and halted progression through reprogramming of the tumor stroma. TCRs represented by single T cell clonotypes were similarly effective only if they shared CDR elements with preferentially selected TCRs in both α and β chains. Selecting candidate TCRs on the basis of these characteristics can help identify TCRs that are potentially therapeutically effective.

Aim: Arsenic has excellent anti-advanced liver cancer effects through a variety of pathways, but its severe systemic toxicity forces the need for a safe and effective delivery strategy.Methods: Based on the chelating metal ion properties of polydopamine (PDA), arsenic was immobilized on an organic carrier, and a M1-like macrophage cell membrane (MM)-camouflaged manganese-arsenic complex mesoporous polydopamine (MnAsOx@MP@M) nanoplatform was successfully constructed. MnAsOx@MP@M was evaluated at the cellular level for tumor inhibition and tumor localization, and in vivo for its anti-liver cancer effect in a Hepa1-6 tumor-bearing mouse model.Results: The nanoplatform targeted the tumor site through the natural homing property of MM, completely degraded and released drugs to kill tumor cells in an acidic environment, while playing an immunomodulatory role in promoting tumor-associated macrophages (TAMs) repolarization.Conclusion: MnAsOx@MP@M has synergistically enhanced the targeted therapeutics against liver cancer via nanotechnology and immunotherapy, and it is expected to become a safe and multifunctional treatment platform in clinical oncology.

The diagnosis and treatment of solid tumors have undergone significant advancements marked by a trend toward increased specificity and integration of imaging and therapeutic functions. The multifaceted nature of inorganic oxide nanomaterials (IONs), which boast optical, magnetic, ultrasonic, and biochemical modulatory properties, makes them ideal building blocks for developing multifunctional nanoplatforms. A promising class of materials that have emerged in this context are peptide-functionalized inorganic oxide nanomaterials (PFIONs), which have demonstrated excellent performance in multifunctional imaging and therapy, making them potential candidates for advancing solid tumor diagnosis and treatment. Owing to the functionalities of peptides in tumor targeting, penetration, responsiveness, and therapy, well-designed PFIONs can specifically accumulate and release therapeutic or imaging agents at the solid tumor sites, enabling precise imaging and effective treatment. This review provides an overview of the recent advances in the use of PFIONs for the imaging and treatment of solid tumors, highlighting the superiority of imaging and therapeutic integration as well as synergistic treatment. Moreover, the review discusses the challenges and prospects of PFIONs in depth, aiming to promote the intersection of the interdisciplinary to facilitate their clinical translation and the development of personalized diagnostic and therapeutic systems by optimizing the material systems.

Moringa oleifera (M. oleifera) is globally recognized for its medicinal properties and offers high-quality, protein-rich seeds. This study aimed to explore the potential of M. oleifera seeds as a significant source of protein-based nanoparticles (PBNPs) using the ultrasonication technique after desolvation and to evaluate their cytotoxicity in the human leukemia cell line (THP-1) for the first time. The properties of the PBNPs were confirmed by dynamic light scattering (DLS), transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FT-IR). The extracted protein from moringa seed cake flour had a significant protein content of 54.20%, and the resulting PBNPs had an average size of 134.3 ± 0.47 nm with a robust zeta potential of -43.15 mV. Notably, our study revealed that PBNPs exhibited cytotoxic potential at high concentrations, especially against the THP-1 human leukemia cell line, which is widely used to study immunomodulatory properties. The inhibitory effect of PBNPs was quantitatively evidenced by a cytotoxicity assay, which showed that a concentration of 206.5 μg mL-1 (log conc. 2.315) was required to inhibit 50% of biological activity. In conclusion, our findings highlight the potential of M. oleifera seeds as a valuable resource in the innovative field of eco-friendly PBNPs by combining traditional medicinal applications with contemporary advancements in protein nanotechnology. However, further studies are required to ensure their biocompatibility.

Emerging evidence indicates the critical roles of circular RNAs in the development of multiple cancers, containing hepatocellular carcinoma (HCC). Herein, our present research reported the biological function and mechanism of circ_0027791 in HCC progression. Circ_0027791, microRNA-496 (miR-496), programmed cell death ligand 1 (PDL1), and methyltransferase-like 3 (METTL3) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability, proliferation, invasion, and sphere formation ability were detected using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, 5-ethynyl-2'-deoxyuridine, transwell, and sphere formation assays. Macrophage polarization was detected using flow cytometry assay. To understand the role of circ_0027791 during the immune escape, HCC cells were cocultured with peripheral blood mononuclear cells or cytokine-induced killer (CIK) cells in vitro. A xenograft mouse model was applied to assess the function of circ_0027791 in vivo. After prediction using circinteractome and miRDB, the binding between miR-496 and circ_0027791 or PDL1 was validated based on a dual-luciferase reporter assay. Interaction between METTL3 and circ_0027791 was determined using methylated RNA immunoprecipitation (MeRIP)-qPCR, RIP-qPCR, and RNA pull-down assays. Circ_0027791, PDL1, and METTL3 expression were upregulated, and miR-496 was decreased in HCC patients and cells. Moreover, circ_0027791 knockdown might repress proliferation, invasion, sphere formation, M2 macrophage polarization, and antitumor immune response. Circ_0027791 knockdown repressed HCC tumor growth in vivo. In mechanism, circ_0027791 functioned as a sponge for miR-496 to increase PDL1 expression. In addition, METTL3 mediated the m6A methylation of circ_0027791 and stabilized its expression. METTL3-induced circ_0027791 facilitated HCC cell progression partly regulating the miR-496/PDL1 axis, which provided a new prognostic and therapeutic marker for HCC.

Melanoma still reaches thousands of new diagnoses per year, and its aggressiveness makes recovery challenging, especially for those with stage III/IV unresectable melanoma. Immunotherapy, emerging as a beacon of hope, stands at the forefront of treatments for advanced melanoma. This review delves into the various immunotherapeutic strategies, prominently featuring cytokine immunotherapy, adoptive cell therapy, immune checkpoint inhibitors, and vaccinations. Among these, immune checkpoint inhibitors, notably anti-programmed cell death-1 (PD-1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) antibodies, emerge as the leading strategy. However, a significant subset of melanoma patients remains unresponsive to these inhibitors, underscoring the need for potent biomarkers. Efficient biomarkers have the potential to revolutionize the therapeutic landscape by facilitating the design of personalized treatments for patients with melanoma. This comprehensive review highlights the latest advancements in melanoma immunotherapy and potential biomarkers at the epicenter of recent research endeavors.

The corpus luteum is a temporary endocrine gland formed in the ovary after ovulation, and it plays a critical role in animal reproductive processes. Tumors rely on the development of an adequate blood supply to ensure the delivery of nutrients and oxygen and the removal of waste products. While angiogenesis occurs in various physiological and pathological contexts, the corpus luteum and tumors share similarities in terms of the signaling pathways that promote angiogenesis. In the corpus luteum and tumors, apoptosis plays a crucial role in controlling cell numbers and ensuring proper tissue development and function. Interestingly, there are similarities between the apoptotic-regulated signaling pathways involved in apoptosis in the corpus luteum and tumors. However, the regulation of apoptosis in both can differ due to their distinct physiological and pathological characteristics. Thus, we reviewed the biological events of the corpus luteum and tumors in similar microenvironments of angiogenesis and apoptosis.

Immunotherapy is a promising approach for preventing postoperative tumor recurrence and metastasis. However, inflammatory neutrophils, recruited to the postoperative tumor site, have been shown to exacerbate tumor regeneration and limit the efficacy of cancer vaccines. Consequently, addressing postoperative immunosuppression caused by neutrophils is crucial for improving treatment outcomes. This study presents a combined chemoimmunotherapeutic strategy that employs a biocompatible macroporous scaffold-based cancer vaccine (S-CV) and a sialic acid (SA)-modified, doxorubicin (DOX)-loaded liposomal platform (DOX@SAL). The S-CV contains whole tumor lysates as antigens and imiquimod (R837, Toll-like receptor 7 activator)-loaded PLGA nanoparticles as immune adjuvants for cancer, which enhance dendritic cell activation and cytotoxic T cell proliferation upon localized implantation. When administered intravenously, DOX@SAL specifically targets and delivers drugs to activated neutrophils in vivo, mitigating neutrophil infiltration and suppressing postoperative inflammatory responses. In vivo and vitro experiments have demonstrated that S-CV plus DOX@SAL, a combined chemo-immunotherapeutic strategy, has a remarkable potential to inhibit postoperative local tumor recurrence and distant tumor progression, with minimal systemic toxicity, providing a new concept for postoperative treatment of tumors.

Breast cancer continues to pose significant challenges in the field of oncology, necessitating innovative treatment approaches. Among these, oncolytic viruses have emerged as a promising frontier in the battle against various types of cancer, including breast cancer. These viruses, often genetically modified, have the unique ability to selectively infect and destroy cancer cells while leaving healthy cells unharmed. Their efficacy in tumor eradication is not only owing to direct cell lysis but also relies on their capacity to activate the immune system, thereby eliciting a potent and sustained antitumor response. While oncolytic viruses represent a significant advancement in cancer treatment, the complexity and adaptability inherent to cancer require a diverse array of therapies. The concept of combining oncolytic viruses with other treatment modalities, such as chemotherapy, immunotherapy, and targeted therapies, has received significant attention. This synergistic approach capitalizes on the strengths of each therapy, thus creating a comprehensive strategy to tackle the heterogeneous and evolving nature of breast cancer. The purpose of this review is to provide an in-depth discussion of preclinical and clinical viro-based combination therapy in the context of breast cancer.

Triple-negative breast cancer (TNBC) presents treatment challenges due to a lack of detectable surface receptors. Natural killer (NK) cell-based adaptive immunotherapy is a promising treatment because of the characteristic anticancer effects of killing malignant cells directly by secreting cytokines and lytic granules. To maximize the cancer recognition ability of NK cells, biomaterial-mediated ex vivo cell surface engineering has been developed for sufficient cell membrane immobilization of tumor-targeting ligands via hydrophobic anchoring. In this study, we optimized amphiphilic balances of NK cell coating materials composed of CD44-targeting hyaluronic acid (HA)-poly(ethylene glycol) (PEG)-lipid to improve TNBC recognition and the anticancer effect. Changes in the modular design of our material by differentiating hydrophilic PEG length and incorporating lipid amount into HA backbones precisely regulated the amphiphilic nature of HA-PEG-lipid conjugates. The optimized biomaterial demonstrated improved anchoring into NK cell membranes and facilitating the surface presentation level of HA onto NK cell surfaces. This led to enhanced cancer targeting via increasing the formation of immune synapse, thereby augmenting the anticancer capability of NK cells specifically toward CD44-positive TNBC cells. Our approach addresses targeting ability of NK cell to solid tumors with a deficiency of surface tumor-specific antigens while offering a valuable material design strategy using amphiphilic balance in immune cell surface engineering techniques.

TNFα and IFNγ (TNF/IFNγ) synergistically induce caspase-8 activation and cancer cell death. However, the mechanism of IFNγ in promoting TNF-initiated caspase-8 activation in cancer cells is poorly understood. Here, we found that in addition to CASP8, CYLD is transcriptionally upregulated by IFNγ-induced transcription factor IRF1. IRF1-mediated CASP8 and CYLD upregulation additively mediates TNF/IFNγ-induced cancer cell death. Clinically, the expression levels of TNF, IFNγ, CYLD, and CASP8 in melanoma tumors are increased in patients responsive to immune checkpoint blockade (ICB) therapy after anti-PD-1 treatment. Accordingly, our genetic screen revealed that ELAVL1 (HuR) is required for TNF/IFNγ-induced caspase-8 activation. Mechanistically, ELAVL1 binds CASP8 mRNA and extends its stability to sustain caspase-8 expression both in IFNγ-stimulated and in basal conditions. Consequently, ELAVL1 determines death receptors-initiated caspase-8-dependent cell death triggered from stimuli including TNF and TRAIL by regulating basal/stimulated caspase-8 levels. As caspase-8 is a master regulator in cell death and inflammation, these results provide valuable clues for tumor immunotherapy and inflammatory diseases.

The successful delivery of therapeutic biomacromolecules into solid tumor holds great challenge due to their high resistance to penetrate through the complex tumor microenvironments. Here, active-transporting nanoparticles are harnessed to efficiently deliver biomacromolecular drugs into solid tumors through cell transcytosis. A series of molecularly precise cyanine 5-cored polylysine G5 dendrimers (Cy5 nanodots) with different peripheral amino acids (G5-AA) is prepared. The capability of these positively charged nanodots to induce cell endocytosis, exocytosis, and transcytosis is evaluated via fluorescence-based high-throughput screen. The optimized nanodots (G5-R) are conjugated with αPD-L1 (a therapeutic monoclonal antibody binding to programmed-death ligand 1) (αPD-L1-G5-R) to demonstrate the nanoparticle-mediated tumor active transport. The αPD-L1-G5-R can greatly enhance the tumor-penetration capability through adsorption-mediated transcytosis (AMT). The effectiveness of αPD-L1-G5-R is tested in treating mice bearing partially resected CT26 tumors, mimicking the local immunotherapy of residual tumors post-surgery in clinic. The αPD-L1-G5-R embedded in fibrin gel can efficiently mediate tumor cell transcytosis, and deliver αPD-L1 throughout the tumor, thereby enhancing immune checkpoint blockade, reducing tumor recurrence, and significantly prolonging the survival time. The active-transporting nanodots are promising platforms for efficient tumor delivery of therapeutic biomacromolecules.

Tumor immunotherapy has become a new hotspot for cancer treatment. Various immunotherapies, such as immune checkpoint inhibitors, oncolytic viruses (OVs), cytokines, and cancer vaccines, have been used to treat tumors. They operate through different mechanisms, along with certain toxicities and side effects. Understanding the mechanisms by which immunotherapy modulates the immune system is essential for improving the efficacy and managing these adverse effects. This article discusses various currently approved cancer immunotherapy mechanisms and related agents approved by the Food and Drug Administration, the European Medicines Agency, and the Medicines and Medical Devices Agency. We also review the latest progress in immune drugs approved by the National Medical Products Administration, including monoclonal antibodies, cytokines, OVs, and chimeric antigen receptor-T cell therapy, to help understand the clinical application of tumor immunotherapy.

Chimeric antigen receptor (CAR) T cell show promise in cancer treatments, but their mechanism of action is not well understood. Decoding the mechanisms used by individual T cells can help improve the efficacy of T cells while also identifying mechanisms of T cell failure leading to tumor escape. Here, we used a suite of assays including dynamic single-cell imaging of cell-cell interactions, dynamic imaging of fluorescent reporters to directly track cytotoxin activity in tumor cells, and scRNA-seq on patient infusion products to investigate the cytotoxic mechanisms used by individual CAR T cells in killing tumor cells. We show that surprisingly, overexpression of the Granzyme B (GZMB) inhibitor, protease inhibitor-9 (PI9), does not alter the cytotoxicity mediated by CD19-specific CAR T cells against either the leukemic cell line, NALM6; or the ovarian cancer cell line, SkOV3-CD19. We designed and validated reporters to directly assay T cell delivered GZMB activity in tumor cells and confirmed that while PI9 overexpression inhibits GZMB activity at the molecular level, this is not sufficient to impact the kinetics or magnitude of killing mediated by the CAR T cells. Altering cytotoxicity mediated by CAR T cells required combined inhibition of multiple pathways that are tumor cell specific: (a) B-cell lines like NALM6, Raji and Daudi were sensitive to combined GZMB and granzyme A (GZMA) inhibition; whereas (b) solid tumor targets like SkOV3-CD19 and A375-CD19 (melanoma) were sensitive to combined GZMB and Fas ligand inhibition. We realized the translational relevance of these findings by examining the scRNA-seq profiles of Tisa-cel and Axi-cel infusion products and show a significant correlation between GZMB and GZMA expression at the single-cell level in a T cell subset-dependent manner. Our findings highlight the importance of the redundancy in killing mechanisms of CAR T cells and how this redundancy is important for efficacious T cells.

Plants offer a promising platform for cost-effective production of biologically active therapeutic glycoproteins. In previous studies, we have developed a plant expression system based on Bamboo mosaic virus (BaMV) by incorporating secretory signals and an affinity tag, which resulted in notably enhanced yields of soluble and secreted fusion glycoproteins (FGs) in Nicotiana benthamiana. However, the presence of fusion tags on recombinant glycoproteins is undesirable for biomedical applications. This study aimed to develop a refined expression system that can efficiently produce tag-free glycoproteins in plants, with enhanced efficacy of mature interferon gamma (mIFNγ) against viruses. To accommodate the specific requirement of different target proteins, three enzymatically or chemically cleavable linkers were provided in this renovated BaMV-based expression system. We demonstrated that Tobacco etch virus (TEV) protease could process the specific cleavage site (LTEV) of the fusion protein, designated as SSExtHis(SP)10LTEV-mIFNγ, with optimal efficiency under biocompatible conditions to generate tag-free mIFNγ glycoproteins. The TEV protease and secretory-affinity tag could be effectively removed from the target mIFNγ glycoproteins through Ni2+-NTA chromatography. In addition, the result of an antiviral assay showed that the tag-free mIFNγ glycoproteins exhibited enhanced biological properties against Sindbis virus, with comparable antiviral activity of the commercialized HEK293-expressed hIFNγ. Thus, the improved BaMV-based expression system developed in this study may provide an alternative strategy for producing tag-free therapeutic glycoproteins intended for biomedical applications.

Profiting from the sustained clinical improvement and prolonged patient survival, immune checkpoint blockade of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has emerged as a revolutionary cancer therapy approach. However, the anti-PD-1/PD-L1 antibodies only achieve a clinical response rate of approximately 20%. Herein, we identified a novel combination strategy that Chinese medicine ginseng-derived ginsenoside Rh2 (Rh2) markedly improved the anti-cancer efficacy of anti-PD-L1 antibody in mice bearing MC38 tumor. Rh2 combined with anti-PD-L1 antibody (combo treatment) further triggered the infiltration, proliferation and activation of CD8+ T cells in the tumor microenvironment (TME). Depletion of CD8+ T cells by mouse CD8 blocking antibody abolished the anti-cancer effect of combo treatment totally. Mechanistically, combo treatment further increased the expression of CXCL10 through activating TBK1-IRF3 signaling pathway, explaining the increased infiltration of T cells. Employing anti- CXC chemokine receptor 3 (CXCR3) blocking antibody prevented the T cells infiltration and abolished the anti-cancer effect of combo treatment. Meanwhile, combo treatment increased the percentage of M1-like macrophages and raised the ratio of M1/M2 macrophages in TME. By comparing the anti-cancer effect of combo treatment among MC38, CT26 and 4T1 tumors, resident T cells were considered as a prerequisite for the effectiveness of combo treatment. These findings demonstrated that Rh2 potentiated the anti-cancer effect of PD-L1 blockade via promoting the T cells infiltration and activation, which shed a new light on the combination strategy to enhance anti-PD-L1 immunotherapy by using natural product Rh2.

Despite intensive developments of adoptive T cell and NK cell therapies, the efficacy against solid tumors remains elusive. Our study demonstrates that macrophage-based cell therapy could be a potent therapeutic option against solid tumors.

To this end, we determine the effect of a natural triterpene glycoside, cucumarioside A2-2 (CA2-2), on the polarization of mouse macrophages into the M1 phenotype, and explore the antitumor activity of the polarized macrophage. The polarization of CA2-2-pretreated macrophages was analyzed by flow cytometry and confocal imaging. The anti-cancer activity of CA2-2 macrophages was evaluated against 4T1 breast cancer cells and EAC cells in vitro and syngeneic mouse model in vivo.

Incubation of murine macrophages with CA2-2 led to polarization into the M1 phenotype, and the CA2-2-pretreated macrophages could selectively target and kill various types of cancer in vitro. Notably, loading near-infrared (NIR) fluorochrome-labeled nanoparticles, MnMEIO-mPEG-CyTE777, into macrophages substantiated that M1 macrophages can target and penetrate tumor tissues in vivo efficiently.

In this study, CA2-2-polarized M1 macrophages significantly attenuated tumor growth and prolonged mice survival in the syngeneic mouse models. Therefore, ex vivo CA2-2 activation of mouse macrophages can serve as a useful model for subsequent antitumor cellular immunotherapy developments.

Cancer stem cells (CSCs) are the most important cause of cancer treatment failure. Traditional cancer treatments, such as chemotherapy and radiotherapy, damage healthy cells alongside malignant cells, leading to severe adverse effects. Therefore, inducing cellular senescence without triggering apoptosis, which further damages healthy cells, may be an alternative strategy. However, there is insufficient knowledge regarding senescence induction in CSCs that show resistance to treatment and stemness properties. The present study aims to elucidate the effects of senescence induction on proliferation, cell cycle, and apoptosis in prostate CSCs and non-CSCs. Prostate CSCs were isolated from DU145 cancer cells using the FACS method. Subsequently, senescence induction was performed in RWPE-1, DU145, prostate CSCs, and non-CSCs by using different concentrations of Doxorubicin (DOX). Cellular senescence was detected using the senescence markers SA-β-gal, Ki67, and senescence-associated heterochromatin foci (SAHF). The effects of senescence on cell cycle and apoptosis were evaluated using the Muse Cell Analyzer, and genes in signaling pathways associated with the apoptotic/necrotic pathway were analyzed by real-time PCR. Prostate CSCs were isolated with 95.6 ± 1.4% purity according to CD133+/CD44+ characteristics, and spheroid formation belonging to stem cells was observed. After DOX-induced senescence, we observed morphological changes, SA-β-gal positivity, SAHF, and the lack of Ki67 in senescent cells. Furthermore; we detected G2/M cell cycle arrest and downregulation of various apoptosis-related genes in senescent prostate CSCs. Our results showed that DOX is a potent inducer of senescence for prostate CSCs, inhibits proliferation by arresting the cell cycle, and senescent prostate CSCs develop resistance to apoptosis.

Tumor development and progression is shaped by the tumor microenvironment (TME), a heterogeneous assembly of infiltrating and resident host cells, their secreted mediators and intercellular matrix. In this context, tumors are infiltrated by various immune cells with either pro-tumoral or anti-tumoral functions. Recently, we published our non-invasive immunization platform DIVA suitable as a therapeutic vaccination method, further optimized by repeated application (DIVA2). In our present work, we revealed the therapeutic effect of DIVA2 in an MC38 tumor model and specifically focused on the mechanisms induced in the TME after immunization. DIVA2 resulted in transient tumor control followed by an immune evasion phase within three weeks after the initial tumor inoculation. High-dimensional flow cytometry analysis and single-cell mRNA-sequencing of tumor-infiltrating leukocytes revealed cytotoxic CD8+ T cells as key players in the immune control phase. In the immune evasion phase, inflammatory CCR2+ PDL-1+ monocytes with immunosuppressive properties were recruited into the tumor leading to suppression of DIVA2-induced tumor-reactive T cells. Depletion of CCR2+ cells with specific antibodies resulted in prolonged survival revealing CCR2+ monocytes as important for tumor immune escape in the TME. In summary, the present work provides a platform for generating a strong antigen-specific primary and memory T cell immune response using the optimized transcutaneous immunization method DIVA2. This enables protection against tumors by therapeutic immune control of solid tumors and highlights the immunosuppressive influence of tumor infiltrating CCR2+ monocytes that need to be inactivated in addition for successful cancer immunotherapy.

Aim: We predicted the modulation of autophagy and apoptosis in response to temozolomide (TMZ) and IFN-γ based on changes in the expression of non-coding RNAs in C6-induced glioblastoma (GBM). Materials & methods: Each rat received an intraperitoneal injection of TMZ (7.5 mg/kg) and/or IFN-γ (50,000 IU). Results: The reduced expression of H19 and colorectal neoplasia differentially expressed (CRNDE) was associated with a reduction in autophagy in response to TMZ, IFN-γ and TMZ + IFN-γ therapy, whereas the decreased level of miR-29a (proapoptotic miRNA) was associated with an increase in apoptosis. Conclusion: It appears that H19 promotes switching from autophagy to apoptosis in response to combination therapy of TMZ and IFN-γ through the miR-29a/autophagy-related protein 9A (ATG9A) pathway in C6-induced GBM.

Oral cancers consist of squamous cell carcinoma (SCC) and other malignancies in the mouth with varying degrees of invasion and differentiation. For many years, different modalities such as surgery, radiation therapy, and classical chemotherapy drugs have been used to control the growth of oral tumors. Nowadays, studies have confirmed the remarkable effects of the tumor microenvironment (TME) on the development, invasion, and therapeutic resistance of tumors like oral cancers. Therefore, several studies have been conducted to modulate the TME in various types of tumors in favor of cancer suppression. Natural products are intriguing agents for targeting cancers and TME. Flavonoids, non-flavonoid herbal-derived molecules, and other natural products have shown promising effects on cancers and TME. These agents, such as curcumin, resveratrol, melatonin, quercetin and naringinin have demonstrated potency in suppressing oral cancers. In this paper, we will review and discuss about the potential efficacy of natural adjuvants on oral cancer cells. Furthermore, we will review the possible therapeutic effects of these agents on the TME and oral cancer cells. Moreover, the potential of nanoparticles-loaded natural products for targeting oral cancers and TME will be reviewed. The potentials, gaps, and future perspectives for targeting TME by nanoparticles-loaded natural products will also be discussed.