Cervical cancer is a public health problem diagnosed in advanced stages, and its main risk factor is persistent high-risk human papillomavirus infection. Today, it is necessary to study new treatment strategies, such as immunotherapy, that use different targets of the tumor microenvironment. In this study, the K14E7E2 mouse was used as a cervical cancer model to evaluate the inhibition of indolamine-2,3-dioxygenase 1 (IDO-1) and C-X-C chemokine receptor type 2 (CXCR-2) as potential anti-tumor targets. DL-1MT and SB225002 were administered for 30 days in two regimens (R1 and R2) based on combination and single therapy approaches to inhibit IDO-1 and CXCR-2, respectively. Subsequently, the reproductive tracts were resected and analyzed to determine the tumor areas, and IHCs were performed to assess proliferation, apoptosis, and CD8 cellular infiltration. Our results revealed that combined inhibition of IDO-1 and CXCR-2 significantly reduces the areas of cervical tumors (from 196.0 mm² to 58.24 mm² in R1 and 149.6 mm² to 52.65 mm² in R2), accompanied by regions of moderate dysplasia, decreased papillae, and reduced inflammation. Furthermore, the proliferation diminished, and apoptosis and intra-tumoral CD8 T cells increased. In conclusion, the combined inhibition of IDO-1 and CXCR-2 is helpful in the antitumor response against preclinical cervical cancer.

In Hutchinson‐Gilford progeria syndrome (HGPS), dysfunctional autophagy results in the accumulation of progerin, a lamin A mutant variant that alters a plethora of processes, inducing senescence and driving premature aging. Therefore, the elimination of progerin through autophagy restoration emerges as a therapeutic intervention against HGPS. However, a comprehensive study of autophagy flux in HGPS remains to be addressed. In this study, the dynamics of autophagy in HGPS fibroblasts were analyzed utilizing different HGPS cell models and experimental approaches. The autophagy‐associated transcriptomic profile was determined, and the autophagy‐lysosome axis was comprehensively analyzed. We demonstrated that progerin induces the formation of autophagosomes but impairs their maturation and subsequent fusion with lysosomes. This alteration is attributed in part to the progerin‐mediated decreased expression of STX17, a marker of mature autophagosomes, and LAMP1, a membrane lysosomal protein, as well as the presence of defective lysosomes. In line with this, the rescue of STX17 and LAMP1 expression improved autophagy flux. Interestingly, treatment of HGPS fibroblasts with Selinexor, an autophagy activator, elicited nuclear accumulation of TFEB and enhanced lysosomal biogenesis and function, thereby activating autophagy. Selinexor treatment improved both autophagosome maturation and autophagosome‐lysosome fusion, which ultimately led to effective autophagic degradation of progerin. In summary, progerin impedes proper autophagy flux, thus preventing its own autophagic degradation, which underscores the relevance of targeting the autophagy‐lysosome pathway to counteract the toxic accumulation of progerin.

Persistent infection with High‐Risk Human Papillomavirus (HR‐HPV), particularly HPV‐16, is the main driver of cervical intraepithelial neoplasia (CIN) and cervical cancer (CC). However, HR‐HPV infection alone is insufficient for malignant progression and nutritional cofactors such as Vitamin A deficiency, may influence cervical neoplasia progression through immune dysregulation. This study aimed to explore the interaction between HPV‐16 E7 oncoprotein expression and severe Vitamin A Deficiency (VAD), as well as the effects of a Vitamin A‐Normal Diet Reintegration (NDR) on adaptive immune regulation in cervical neoplasia using the K14E7 preclinical murine model. We found that VAD worsening cervical epithelial changes and impairs the cytotoxic ability of CD8 ⁺ T cells, which is marked by lower levels of granzyme B and increased expression of PI‐9. These changes were accompanied by increase F4/80 ⁺ macrophage infiltration and elevated Foxp3 expression, suggesting enhanced Tregs immunosuppressor activity. Distinctly, NDR induced partial recovery of cervical epithelium architecture and the effector function of CD8 ⁺ T cells. Our results highlight Vitamin A as a key immunomodulator that influences the balance between immune surveillance and immune evasion of HPV‐associated cervical carcinogenesis and suggests its potential relevance for preventive or adjuvant treatments in populations at high risk of CC.

Cancer is the second leading cause of death worldwide. Mutations in the TP53 gene lead to a loss of tumor suppressor function and an oncogenic gain of function for the protein, resulting in a more invasive, metastatic, and chemoresistant phenotype. Diverse structural studies have demonstrated that mutant p53 core domain unfolding is not irreversible. Thus, reactivation toward its wild-type-like conformation or inactivation of its mutant p53 capacities may restore the expression of genes in its tumor suppressor pathways, resulting in enhanced responses to current therapies. Resveratrol (3,4′,5-trihydroxy-trans-stilbene) is a phytoalexin naturally found in more than 70 plant species that has widely proven antiproliferative and pro-apoptotic properties, as well as a capacity to reverse multidrug resistance in various cancer types. Interestingly, it has recently been demonstrated that resveratrol directly interacts with the p53 core domain and reduces mutant p53 aberrant aggregation. In this context, our study aims to elucidate whether resveratrol may induce antiproliferative and pro-apoptotic pathways regardless of a mutant background. We observed that resveratrol has an antiproliferative effect in cancer cells, independent of p53 status, and leads to apoptosis after 48 h of treatment. Resveratrol also induces the expression of p53 tumor suppressor target genes, which are involved in cell cycle arrest and apoptosis. Even though the previous effects are more significant in cells expressing wild-type p53, resveratrol drastically sensitizes all cancer cell lines, regardless of p53 status, to cisplatin treatment, making it a promising enhancer compound to overcome chemoresistance associated with p53.