Table 1.

Components of the tumor microenviroment.

	Cell Type and Subtype	Function and Location	Prognostic and/or Predictive Value	Markers	Refs
Immune system	Lymphocytes T lymphocytes and cytotoxic T cells Helper T cells, and regulatory T cells, Memory T cells	Once activated, naive CD4+ and CD8+ T lymphocytes, present in the blood and lymphoid organs, generate different cell subsets to perform cytotoxic functions. CD8+ subsets: Tc1 and Tc2. CD4+ subsets: Th1, Th2, Th17, and Treg (Foxp3). Following exposure to an antigen, a small subset of effector T cells differentiate into memory cells. Memory T cells maintain their antigen specificity and help to amplify the immune response during antigen re-exposure.	NAC All subtypes: higher TIL infiltration increases pCR rates Adjuvant treatment TNBC: increase the DFS for each 10% increment of sTILs TNBC and ER-/Her2+: the presence of CD8+ cells increases breast-cancer-specific survival ER+: the presence of CD8+ decreases DFS	T lymphocyte: CD69, CD25, CD45RO, OX40, 4-1BBL, CD95, Granzyme B, and Perforin, CD44 Memory T lymphocyte: CCR7, CD62L, CD45RO, CD45RA, CD95, CD127, CD28, and Granzyme B	[13,14,16,17,20,21,22,23,24,25,26]
	Macrophages	Phagocytic cells that consume foreign pathogens and cancer cells. Stimulate the responses of other immune cells. Migrate from blood vessels into tissues.	Increased TAMs decrease the OS Increased TAMs CD68+ decrease the DFS and breast-cancer-specific survival	CD68, CD64, CD11b, and colony-stimulating factor 1 receptor	[34,35,36]
Other stromal components	Fibroblasts	Fibroblasts create and maintain anatomically diverse extracellular-matrix (ECM)-rich connective tissues to support a broad range of essential organ functions. Fibroblasts provide essential niches and positional information for neighboring cells via biochemical cues in the ECM and the regulated secretion of soluble mediators such as cytokines, growth factors, and metabolites. In addition, fibroblasts serve as the progenitors of specialized mesenchymal cell types, such as bone-forming osteoblasts or lipid-filled adipocytes during embryonic development, adult homeostasis, and injury, repair, and remodeling.	Higher αSMA+ fibroblasts decrease recurrence-free survival and breast cancer-specific survival and serve as a predictor of metastasis; the CAF gene signature is associated with an adverse outcome The ER+: active stroma signature decreases the OS TGFBR2+ cells increase the DFSCytoplasmic Gli1: shorter survival	Fibroblast activation protein α, α smooth muscle actin, microfibril-associated protein 5, collagen type XI alpha 1 chain, tenascin-C, podoplanin, integrin α11β1, and neural/glial antigen 2	[53,55,57,59]
	Vasculature	Tumor angiogenesis entails the development of new blood vessels from established vascular beds. Hypoxia and nutrient deprivation trigger an “angiogenic switch” to allow the tumor to progress. The resulting vessel network is leaky, unorganized, and ill-perfused, determining how cancer cells escape anticancer immunosurveillance, metastasize, and respond to therapy.	High HIF-a1 expression, shorter DFS and OS. Increased MVD decrease DFS and OS	VEGFR, integrin αvβ3, CD44-related antigen, fibronectin ED-B domain, endoglin, endosialin, E-selectin, and vascular cell adhesion molecule 1	[62,68]
	Adipocytes	Adipose tissue is a connective tissue mainly composed of adipocytes. Adipocytes are energy-storing cells that contain large globules of fat known as lipid droplets surrounded by a structural network of fibers. At the cancer invasion front, adipocytes undergo lipolysis and transform into CAAs. CAAs can secrete a variety of adipokines and release free fatty acids and exosomes to cancer cells for metabolic reprogramming.	Increased BMI higher risk of mortality. Obesity decreases OS	Leptin, Hoxc8, Hoxc9, Ucp1, CIDEA, PRDM16, Zic1, Lhx8, Eva1 Epsti1 Cd137, Tmem26, Tbx1, Cited1, and Shox2	[66]