Mutant P53 in the formation and progression of the tumor microenvironment: Friend or foe.

TP53 is the most frequently mutated gene in human cancer. It encodes the tumor suppressor protein p53, which suppresses tumorigenesis by acting as a critical transcription factor that can induce the expression of many genes controlling a plethora of fundamental cellular processes, including cell cycle progression, survival, apoptosis, and DNA repair. Missense mutations are the most frequent type of mutations in the TP53 gene. While these can have variable effects, they typically impair p53 function in a dominant-negative manner, thereby altering intra-cellular signaling pathways and promoting cancer development. Additionally, it is becoming increasingly apparent that p53 mutations also have non-cell autonomous effects that influence the tumor microenvironment (TME). The TME is a complex and heterogeneous milieu composed of both malignant and non-malignant cells, including cancer-associated fibroblasts (CAFs), adipocytes, pericytes, different immune cell types, such as tumor-associated macrophages (TAMs) and T and B lymphocytes, as well as lymphatic and blood vessels and extracellular matrix (ECM). Recently, a large body of evidence has demonstrated that various types of p53 mutations directly affect TME. They fine-tune the inflammatory TME and cell fate reprogramming, which affect cancer progression. Notably, re-educating the p53 signaling pathway in the TME may be an effective therapeutic strategy in combating cancer. Therefore, it is timely to here review the recent advances in our understanding of how TP53 mutations impact the fate of cancer cells by reshaping the TME.

Asl ER ，Rostamzadeh D ，Duijf PHG ，Mafi S ，Mansoori B ，Barati S ，Cho WC ，Mansoori B ... -  《-》

p53's Extended Reach: The Mutant p53 Secretome.

Pavlakis E ，Stiewe T 《Biomolecules》

Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment.

Cui Y ，Guo G 《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

TP53 to mediate immune escape in tumor microenvironment: an overview of the research progress.

Increasing evidence suggests that key cancer-causing driver genes continue to exert a sustained influence on the tumor microenvironment (TME), highlighting the importance of immunotherapeutic targeting of gene mutations in governing tumor progression. TP53 is a prominent tumor suppressor that encodes the p53 protein, which controls the initiation and progression of different tumor types. Wild-type p53 maintains cell homeostasis and genomic instability through complex pathways, and mutant p53 (Mut p53) promotes tumor occurrence and development by regulating the TME. To date, it has been wildly considered that TP53 is able to mediate tumor immune escape. Herein, we summarized the relationship between TP53 gene and tumors, discussed the mechanism of Mut p53 mediated tumor immune escape, and summarized the progress of applying p53 protein in immunotherapy. This study will provide a basic basis for further exploration of therapeutic strategies targeting p53 protein.

Zhu KL ，Su F ，Yang JR ，Xiao RW ，Wu RY ，Cao MY ，Ling XL ，Zhang T ... -  《-》

Metabolic reprogramming and crosstalk of cancer-related fibroblasts and immune cells in the tumor microenvironment.

It is notorious that cancer cells alter their metabolism to adjust to harsh environments of hypoxia and nutritional starvation. Metabolic reprogramming most often occurs in the tumor microenvironment (TME). TME is defined as the cellular environment in which the tumor resides. This includes surrounding blood vessels, fibroblasts, immune cells, signaling molecules and the extracellular matrix (ECM). It is increasingly recognized that cancer cells, fibroblasts and immune cells within TME can regulate tumor progression through metabolic reprogramming. As the most significant proportion of cells among all the stromal cells that constitute TME, cancer-associated fibroblasts (CAFs) are closely associated with tumorigenesis and progression. Multitudinous studies have shown that CAFs participate in and promote tumor metabolic reprogramming and exert regulatory effects via the dysregulation of metabolic pathways. Previous studies have demonstrated that curbing the substance exchange between CAFs and tumor cells can dramatically restrain tumor growth. Emerging studies suggest that CAFs within the TME have emerged as important determinants of metabolic reprogramming. Metabolic reprogramming also occurs in the metabolic pattern of immune cells. In the meanwhile, immune cell phenotype and functions are metabolically regulated. Notably, immune cell functions influenced by metabolic programs may ultimately lead to alterations in tumor immunity. Despite the fact that multiple previous researches have been devoted to studying the interplays between different cells in the tumor microenvironment, the complicated relationship between CAFs and immune cells and implications of metabolic reprogramming remains unknown and requires further investigation. In this review, we discuss our current comprehension of metabolic reprogramming of CAFs and immune cells (mainly glucose, amino acid, and lipid metabolism) and crosstalk between them that induces immune responses, and we also highlight their contributions to tumorigenesis and progression. Furthermore, we underscore potential therapeutic opportunities arising from metabolism dysregulation and metabolic crosstalk, focusing on strategies targeting CAFs and immune cell metabolic crosstalk in cancer immunotherapy.

Zhu Y ，Li X ，Wang L ，Hong X ，Yang J ... -  《Frontiers in Endocrinology》