The ability of tumor cells to evade the immune system is one of the main challenges we confront in the fight against cancer. Multiple strategies have been developed to counteract this situation, including the use of immunostimulant molecules that play a key role in the anti-tumor immune response. Such a response needs to be tumor-specific to cause as little damage as possible to healthy cells and also to track and eliminate disseminated tumor cells. Therefore, the combination of immunostimulant molecules and tumor-associated antigens has been implemented as an anti-tumor therapy strategy to eliminate the main obstacles confronted in conventional therapies. The immunostimulant 4-1BBL belongs to the tumor necrosis factor (TNF) family and it has been widely reported as the most effective member for activating lymphocytes. Hence, we will review the molecular, pre-clinical, and clinical applications in conjunction with tumor-associated antigens in antitumor immunotherapy, as well as the main molecular pathways involved in this association.

Human papillomaviruses (HPVs) are responsible for about 25% of cancer cases worldwide. HPV-16 E7 antigen is a tumor-associated antigen (TAA) commonly expressed in HPV-induced tumors; however, it has low immunogenicity. The interaction of 4-1BBL with its receptor induces pleiotropic effects on innate, adaptive, and regulatory immunity and, if fused to TAAs in DNA vaccines, can improve the antitumor response; however, there is low transfection and antitumor efficiency. Oncolytic virotherapy is promising for antitumor gene therapy as it can be selectively replicated in tumor cells, inducing cell lysis, and furthermore, tumor cell debris can be taken in by immune cells to potentiate antitumor responses. In this study, we expressed the immunomodulatory molecule SA-4-1BBL fused to E7 on an oncolytic adenovirus (OAd) system. In vitro infection of TC-1 tumor cells and NIH-3T3 non-tumor cells with SA/E7/4-1BBL OAd demonstrated that only tumor cells are selectively destroyed. Moreover, protein expression is targeted to the endoplasmic reticulum in both cell lines when a signal peptide (SP) is added. Finally, in an HPV-induced cancer murine model, the therapeutic oncolytic activity of OAd can be detected, and this can be improved when fused to E7 and SP.

Caloric restriction (CR) and its related alternatives have been shown to be the only interventions capable of extending lifespan and decreasing the risk of cancer, along with a reduction in burden in pre-clinical trials. Nevertheless, the results from clinical trials have not been as conclusive as the pre-clinical results. Recognizing the challenges associated with long-term fasting, the application of caloric restriction mimetics (CRMs), pharmacological agents that mimic the molecular effects of CR, to harness the potential benefits while overcoming the practical limitations of fasting has resulted in an interesting alternative. This review synthesizes the findings of diverse clinical trials evaluating the safety and efficacy of CR and CRMs. In dietary interventions, a fast-mimicking diet was the most tolerated to reduce tumoral growth markers and chemotherapy side effects. CRMs were well tolerated, and metformin and aspirin showed the most promising effect in reducing cancer risk in a selected group of patients. The application of CR and/or CRMs shows promising effects in anti-cancer therapy; however, there is a need for more evidence to safely include these interventions in standard-of-care therapies.

The endoplasmic reticulum (ER) is where the major histocompatibility complex (MHC) class I molecules are loaded with epitopes to cause an immune cellular response. Most of the protein antigens are degraded in the cytoplasm to amino acids and few epitopes reach the ER. Antigen targeting of this organelle by Calreticulin (CRT) fusion avoids this degradation and enhances the immune response. We constructed a recombinant adenovirus to express the E7 antigen with an ER‐targeting signal peptide (SP) plus an ER retention signal (KDEL sequence). In cell‐culture experiments we demonstrated that this new E7 antigen, SP‐E7‐KDEL, targeted the ER. Infection of mice with this recombinant adenovirus that expresses SP‐E7‐KDEL showed interferon induction and tumour‐protection response, similar to that provided by an adenovirus expressing the E7 antigen fused to CRT. This work demonstrated that just by adding a SP and the KDEL sequence, antigens can be targeted and retained in the ER with a consequent enhancement of immune response and tumour protection. These results will have significant clinical applications.

Background: Although the safety of COVID-19 vaccines has been demonstrated in clinical trials, real-world pharmacovigilance remains essential to detect rare or unexpected adverse events following immunization (AEFI). In Mexico, the national AEFI surveillance system is in place, yet there is limited analysis of state-level data. Objective: To characterize AEFI related to five COVID-19 vaccines and identify factors associated with AEFI type and seriousness in Nuevo León, Mexico. Methods: A retrospective analysis of the State of Nuevo León AEFI database was conducted, including all AEFI reports between December 2020 and June 2022 (n = 2213). Data included patient sex, age, vaccine type (Pfizer/BioNTech, AstraZeneca, Sinovac, Moderna, CanSino), number of doses (1 or ≥2), symptom categories, and AEFI seriousness. Symptoms were classified as local or systemic and grouped by organ systems. Descriptive analysis and binary multivariate logistic regression were used to examine associations between demographic and vaccine-related factors with AEFI type and severity. Odds ratios (OR) with 95% confidence intervals (CI) were estimated. Results: Most AEFI reports involved females aged 19–59 years and occurred after the first vaccine dose. The most frequently reported unexpected adverse events (UAEs) were mild to moderate, including injection-site reactions, headache, chills, fatigue, nausea, fever, dizziness, weakness, myalgia, and tachycardia. The Pfizer/BioNTech vaccine was associated with higher odds of arm pain and lower odds of hemorrhagic events. Receiving ≥2 doses increased the odds of arm pain and systemic symptoms. Less than 3% of AEFIs were classified as serious. Older adults (≥65 years) and second vaccine doses were associated with increased odds of a serious AEFI, while female sex and receiving the Pfizer/BioNTech vaccine were associated with reduced odds. Conclusions: In Nuevo León, most AEFIs related to COVID-19 vaccination were mild to moderate and resolved without complications. Serious AEFIs were uncommon, with older age and second doses associated with higher risk, and female sex and Pfizer/BioNTech vaccination associated with lower risk. These findings provide a local perspective on vaccine safety that complements national and international evidence.