Breast Cancer Treatment Strategies Targeting the Tumor Microenvironment: How to Convert "Cold" Tumors to "Hot" Tumors

Abstract

Breast cancer characterized as "cold tumors" exhibit low levels of immune cell infiltration, which limits the efficacy of conventional immunotherapy. Recent studies have focused on strategies using nanotechnology combined with tumor microenvironment modulation to transform "cold tumors" into "hot tumors". This approach involves the use of functionalized nanoparticles that target and modify the tumor microenvironment to promote the infiltration and activation of antitumor immune cells. By delivering immune activators or blocking immunosuppressive signals, these nanoparticles activate otherwise dormant immune responses, enhancing tumor immunogenicity and the therapeutic response. These strategies not only promise to increase the response rate of breast cancer patients to existing immunotherapies but also may pave new therapeutic avenues, providing a new direction for the immunotherapy of breast cancer.

Keywords: breast cancer; immunotherapy; nano-immunotherapy; nanoparticles; novel agents; target therapy; tumor microenvironment.

Figure 1

Transforming cold tumors into hot tumors by modulating the cancer–immunity cycle. The cancer–immunity cycle starts with the release of cancer cell antigens (I), followed by their presentation to T cells by dendritic cells (II). This leads to T cells activation and their migration to the tumor site, where they infiltrate, recognize and kill the cancer cells (III–VII). The destruction of cancer cells releases new antigens, perpetuating the cycle and sustaining the immune response against the tumor (VII–I). Each step in this cycle offers potential targets for enhancing immunotherapy treatments.

Figure 2

The biological functions and secreted cytokines of tumor-associated macrophages (TAMs). (1) Angiogenesis: TAMs promote the formation of new blood vessels, which supply tumors with oxygen and nutrients. (2) Immunosuppression: TAMs suppress immune responses against tumors by producing immunosuppressive cytokines. (3) Cell Survival and Proliferation: TAMs release growth factors that enhance tumor cell survival and proliferation. (4) Tumor Metabolism: TAMs adapt the tumor metabolism for rapid growth by enhancing the nutrient availability and adapting to low oxygen. (5) Treatment Resistance: TAMs promote resistance by altering the tumor environment and reducing the effectiveness of therapies. (6) Metastasis: TAMs assist in cancer metastasis by degrading extracellular matrices, facilitating the tumor cell invasion of other tissues.

Figure 3

The immune regulation of DC in tumor microenvironment. cDCs migrate to lymph nodes to prime T cells: cDC1s activate both CD4⁺ and CD8⁺ T cells, while cDC2s primarily activate CD4⁺ T cells. cDC1s produce CXCL9 and CXCL10, attracting activated T cells via CXCR3. DCs also regulate T cells activation through various co-stimulatory molecules. Interaction with NK cells enhances this dynamic, with NK cells promoting cDC1 recruitment and activation via chemokines like CCL5 and XCL1 and cDC1s, in turn, boosting NK cell function with IL-12. After antigen uptake, cDCs can become regulatory DCs expressing PD-L1, modulating immune responses towards either suppression or tolerance.

Figure 4

Diagrammatic illustration of selected pro-tumorigenic roles of cancer-associated fibroblasts (CAFs).